U.S. patent number 10,912,786 [Application Number 15/247,539] was granted by the patent office on 2021-02-09 for silyl monomers capable of multimerizing in an aqueous solution, and methods of using same.
This patent grant is currently assigned to Cornell University, Purdue Research Foundation. The grantee listed for this patent is Cornell University, Purdue Research Foundation. Invention is credited to Lee Daniel Arnold, Francis Barany, Donald E. Bergstrom, Sarah F. Giardina, Maneesh Pingle.
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United States Patent |
10,912,786 |
Barany , et al. |
February 9, 2021 |
Silyl monomers capable of multimerizing in an aqueous solution, and
methods of using same
Abstract
Described herein are silyl monomers capable of forming a
biologically useful multimer when in contact with one, two, three
or more other monomers in an aqueous media. Such multimer forming
associations of monomers may be promoted by the proximal binding of
the monomers to their target biomolecule(s). In one aspect, such
monomers may be capable of binding to another monomer in an aqueous
media (e.g. in vivo) to form a multimer, (e.g. a dimer).
Contemplated monomers may include a ligand moiety, a linker
element, and a connector element that joins the ligand moiety and
the linker element. In an aqueous media, such contemplated monomers
may join together via each linker element and may thus be capable
of modulating one or more biomolecules substantially
simultaneously, e.g., modulate two or more binding domains on a
protein or on different proteins.
Inventors: |
Barany; Francis (New York,
NY), Pingle; Maneesh (New York, NY), Bergstrom; Donald
E. (West Lafayette, IN), Giardina; Sarah F. (New York,
NY), Arnold; Lee Daniel (Mt. Sinai, NY) |
Applicant: |
Name |
City |
State |
Country |
Type |
Cornell University
Purdue Research Foundation |
Ithaca
West Lafayette |
NY
IN |
US
US |
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Assignee: |
Cornell University (Ithaca,
NY)
Purdue Research Foundation (West Lafayette, IN)
|
Family
ID: |
1000005349291 |
Appl.
No.: |
15/247,539 |
Filed: |
August 25, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20170080001 A1 |
Mar 23, 2017 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14110060 |
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PCT/US2012/032813 |
Apr 9, 2012 |
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61473091 |
Apr 7, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/695 (20130101); A61K 47/55 (20170801); C07F
7/10 (20130101) |
Current International
Class: |
A61K
31/695 (20060101); C07F 7/10 (20060101); A61K
47/55 (20170101) |
References Cited
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WO |
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Dec 2005 |
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WO |
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2008/131921 |
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Nov 2008 |
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WO |
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Feb 2009 |
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WO |
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Feb 2009 |
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WO |
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WO |
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WO |
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WO |
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2013058824 |
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Apr 2013 |
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WO |
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WO-2015081280 |
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Jun 2015 |
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WO |
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|
Primary Examiner: Jarrell; Noble E
Attorney, Agent or Firm: Troutman Pepper Hamilton Sanders
LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser.
No. 14/110,060, filed Apr. 9, 2012, which is a national stage
application, submitted under 35 U.S.C. .sctn. 371, of PCT
Application No. PCT/US2012/032813, filed Apr. 9, 2012, which claims
priority to U.S. Provisional Application No. 61/473,091, filed Apr.
7, 2011, each of which is hereby incorporated by reference in its
entirety.
Claims
What is claimed is:
1. A dimer compound represented by:
X.sup.1--Y.sup.1--Z.sup.1*--O--Z.sup.2*--Y.sup.2--X.sup.2 (Formula
III) or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein X.sup.1 is a pharmacophore; Y.sup.1 is selected from the
group consisting of: (a) a covalent bond; (b) a bivalent linker
selected from the group consisting of: (i) substituted or
unsubstituted C.sub.1-C.sub.10 alkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted arylene,
substituted or unsubstituted heteroarylene, acylene, sulfonyl,
sulfonamide, phosphate, ester, carbonate, carbamate, or amide; and
(ii) bivalent C.sub.1-10 saturated or unsaturated, straight or
branched, hydrocarbon chain, wherein one, two, three, or four
methylene units of bivalent C.sub.1-10 are optionally and
independently replaced by cyclopropylene, --NR--, --N(R)C(O)--,
--C(O)N(R)--, --N(R)SO.sub.2--, --SO.sub.2N(R)--, --O--, --C(O)--,
--OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR)--, phenylene, or a mono or bicyclic heterocyclene
ring, wherein R is selected from the group consisting of hydrogen,
aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, and
heteroarylalkyl; and (c) a pharmaceutically acceptable polymer;
X.sup.2 is a pharmacophore; Y.sup.2 is selected from the group
consisting of: (a) a covalent bond; (b) a bivalent linker selected
from the group consisting of: (i) substituted or unsubstituted
C.sub.1-C.sub.10 alkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted arylene, substituted or
unsubstituted heteroarylene, acylene, sulfonyl, sulfonamide,
phosphate, ester, carbonate, carbamate, or amide; and (ii) bivalent
C.sub.1-10 saturated or unsaturated, straight or branched,
hydrocarbon chain, wherein one, two, three, or four methylene units
of bivalent C.sub.1-10 are optionally and independently replaced by
cyclopropylene, --NR--, --N(R)C(O)--, --C(O)N(R)--,
--N(R)SO.sub.2--, --SO.sub.2N(R)--, --O--, --C(O)--, --OC(O)--,
--C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR)--, phenylene, or a mono or bicyclic heterocyclene
ring, wherein R is selected from the group consisting of hydrogen,
aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, and
heteroarylalkyl; and (c) a pharmaceutically acceptable polymer; and
Z.sup.1* and Z.sup.2*, independently, for each occurrence, are:
##STR00226## wherein ##STR00227## represents an attachment point to
Y if Y is not a covalent bond, or to X if Y is a covalent bond;
##STR00228## represents an attachment point to O; BB, independently
for each occurrence, is a one- or two-ringed aryl or heteroaryl
moiety, wherein the aryl or heteroaryl moiety is optionally
substituted with one, two, three or more groups represented by
R.sup.BB; wherein: each R.sup.BB is independently selected, for
each occurrence, from the group consisting of hydrogen, halogen,
hydroxyl, amino, thiol, S--CH.sub.3, --COOH, --CONHR', substituted
or unsubstituted aliphatic, substituted or unsubstituted
heteroaliphatic, --C.sub.1-4 alkyl, --O--C.sub.1-4 alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, and --C(O)--NR.sup.aR.sup.b; wherein: R'
is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic; and R.sup.a and
R.sup.b are independently selected, for each occurrence, from the
group consisting of hydrogen and C.sub.1-4alkyl; W.sup.1,
independently for each occurrence, is absent or selected from the
group consisting of --C.sub.1-4alkylene, --C.sub.2-6alkenylene-,
and --O--C.sub.1-4alkylene-; and R.sup.1 and R.sup.2 are
independently for each occurrence, C.sub.1-6 alkyl.
2. The dimer compound of claim 1, wherein X.sup.1 and X.sup.2 are
different.
3. The dimer compound of claim 1, wherein W.sup.1 is absent.
4. The dimer compound of claim 1, wherein BB is phenyl or
heteroaryl.
5. The dimer compound of claim 1 wherein R.sup.1 and R.sup.2 are
methyl.
6. The dimer compound of claim 1, wherein the dimer binds to a
target biomolecule with greater affinity than does its
corresponding monomers; the dimer is capable of interacting with a
larger target site than its corresponding monomers are capable of
interacting with; the target comprises two protein domains
separated by a distance such that the dimer, but not its
corresponding monomers, is capable of binding to both domains
essentially simultaneously; the apparent IC.sub.50 of the dimer is
lower than the apparent IC.sub.50 of its corresponding monomers;
the ratio of the smaller of the apparent IC.sub.50 of each
corresponding monomer to the apparent IC.sub.50 of the dimer is at
least 3.0; the dimer has different fluorescent properties than its
corresponding monomers; the dimer has greater fluorescent
brightness at a particular wavelength than its corresponding
monomers; the dimer's peak fluorescence is red- or blue-shifted
relative to that of its corresponding monomers; the dimer has
stronger inhibition than X.sup.1 alone, X.sup.2 alone, and/or its
corresponding monomers alone; the dimer has greater activation than
X.sup.1 alone, X.sup.2 alone, and/or its corresponding monomers
alone; and/or the dimer creates a binding entity covering a larger
surface area of a target than the surface area covered by X.sup.1
alone, X.sup.2 alone, and/or its corresponding monomers alone.
7. A method of treating a disease associated with a target protein
or a target protein-protein interaction in a patient in need
thereof comprising: administering to said patient the dimer
compound of claim 1, wherein upon administration, the dimer
compound binds to one, two, three or more protein domains in said
target protein, or to at least one protein domain in each of the
proteins involved in the protein-protein interaction.
8. A method of modulating two or more target biomolecule domains
substantially simultaneously comprising: contacting said
biomolecular target with the dimer compound of claim 1, wherein
X.sup.1 is a first ligand moiety capable of binding to and
modulating a first target biomolecule domain; and X.sup.2 is a
ligand moiety capable of binding to and modulating a second target
biomolecule domain.
9. A method of treating a disease associated with two or more
target biomolecule domains in a patient in need thereof comprising:
administering to said patient the dimer compound of claim 1,
wherein X.sup.1 is a first ligand moiety capable of binding to and
modulating a first target biomolecule domain; and X.sup.2 is a
second ligand moiety capable of binding to and modulating a second
target biomolecule domain.
10. The dimer compound of claim 1, wherein Z.sup.1* and Z.sup.2*,
independently for each occurrence, are: ##STR00229##
11. The dimer compound of claim 1, represented by: ##STR00230##
12. The dimer compound of claim 1, wherein
X.sup.1--Y.sup.1--Z.sup.1*-- and X.sup.2--Y.sup.2--Z.sup.2*-- are
different.
13. The dimer compound of claim 1, wherein
X.sup.1--Y.sup.1--Z.sup.1*-- and X.sup.2--Y.sup.2--Z.sup.2*-- are
the same.
14. The dimer compound of claim 1, wherein Z.sup.1* and Z.sup.2*
are the same.
15. The dimer compound of claim 1, wherein W.sup.1, independently
for each occurrence, is absent or --C.sub.1-4alkylene-.
16. The dimer compound of claim 1, wherein each R.sup.BB is
independently selected, for each occurrence, from the group
consisting of hydrogen, halogen, hydroxyl, amino, thiol, --COOH,
--CONHR', substituted or unsubstituted aliphatic, substituted or
unsubstituted heteroaliphatic, --C.sub.1-4alkyl,
--O--C.sub.1-4alkyl, --N(R.sup.a)--C.sub.1-4alkyl,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl, and
--C(O)--NR.sup.aR.sup.b; wherein: R' is independently selected, for
each occurrence, from the group consisting of hydrogen, substituted
or unsubstituted aliphatic, and substituted or unsubstituted
heteroaliphatic; and R.sup.a and R.sup.b are independently
selected, for each occurrence, from the group consisting of
hydrogen and C.sub.1-4 alkyl.
17. The dimer compound of claim 1, wherein X.sup.1 and X.sup.2 are
each, independently, selected from the group consisting of tryptase
inhibitors, ribosome inhibitors, antibiotics,
(2S,4R)-4-methylglutamic acid, (VPPPVPPRRR (SEQ ID NO: 9))2K, 1,25
dihydroxy vitamin D, 17-beta-estradiol, 19S,
2',3'-Dideoxyadenosine, 2',5'-Dideoxyadenosine, 2-phenyl indole,
A-371191, ABT-737, ABT-751, Acetylcholine, acidic phospholipids,
aconitine, Ac-SpYVNVQ-NH2 (SEQ ID NO: 10), adalimumab,
aeroplysinin-1, AG18, AG82, AG99, AG112, AG126, AG213, AG490,
AG494, AG527, AG555, AG556, AG014699, ALB109564, albuterol,
amphiregulin, anti-EGFR antibody C225, apigenin, ATM, ATPA, ATR,
atropine, axitinib, AZD2281, BAD, basiliximab, BAY 50-4798, BAY K
8644, benomyl, betacellulin, bevacizumab, BH3I-1, BI-78D3,
Bortezomib, BRCT, brompheniramine, BS-201, BS-401, butoxamine,
caffeine, CAK, calyculin A, Caproctamine, CARD, caspase, Cdc37,
Celastrol, Cetirizine, CGP 28392, Chk1, Chk2, Chlorotrianisene,
chlorpheniramine, Cholera toxin, CNQX, curcumin, cyclin A, cyclin
E, D24851, D64131, daclizumab, DD, Desloratadine, diacylglycerol,
Dienestrol, Diethylstilbestrol, dihydropyridine, diphenhydramine,
di-ubiquitin, domoic acid, doxylamine, Epidermal Growth Factor,
epinephrine, epiregulin, ERK1-2, estradiol, estramustine, Estriol,
estrone, etanercept, everolimus, farnesylthiosalicylic acid,
Fexofenadine, FJ9, fluorouracil, Fmoc-Glu-Tyr-Aib-Asn-NH.sub.2 (SEQ
ID NO: 5), forskolin, Fosfestrol, FtsZ, fumonisin B, G proteins,
Galantamine, Glutamate, Granzyme B, GS7904L,
H-GYGRKKRRQRRR-G-MPKKKPTPIQLNP-NH.sub.2 (SEQ ID NO: 2), Histamine,
HL198, HPV E1, ICI 164,384, IGFII, IL2R, indandiones, infliximab,
INO-1001, interferon, iodowillardiine, IP3, ipratropium, JNK,
kainic acid, Keoxifene, KLVFF (SEQ ID NO: 3), K-ras, LBH589,
lincosamides, Linezolid, Loratadine, LSNPTX-NH.sub.2 (SEQ ID NO:
7), LVFFA (SEQ ID NO: 4), LY290181, LY293558, LY294486, LY339434,
LYASSNPAX-NH.sub.2 (SEQ ID NO: 8), MDL-12330A, MDM2, MEK, Memoquin,
Mepitiostane, Meriolin, Metrifonate, MI-63, MI-219, MIRA-1, m114,
m115, m116, mLST8/G.beta.L, mono-ubiquitin, Naphthamides,
Neostigmine, neuregulins, nifedipine, NKY80, nodularin, nolatrexed,
norepinephrine, NSC 348900, NSC668036, Nutlins, P1-30, p38 MAPK,
p53, pazopanib, PB1, PD98059, PD153035, PDZ, pemetrexed,
Peptidimer-c, perifosine, phorbol esters, Phosphatidylinositol,
Phosphatidylinositol 3-phosphate, Phosphatidylinositol 4-phosphate,
Phosphatidylinositol 5-phosphate, Phosphatidylinositol
(3,4)-biphosphate, Phosphatidylinositol (3,5)-biphosphate,
Phosphatidylinositol (4,5)-biphosphate, Phosphatidylinositol
(1,4,5)-triphosphate, Phosphatidylinositol (3,4,5)-triphosphate,
Physostigmine, Pifithrin-a, Pilocarpine, PLX4720, podophyllotoxin,
PPXXF motifs, PQIP, PRIMA-1, propranolol, PyD, pyrilamine, R18,
raltitrexed, Ranibizumab, Rapamycin, Raptor, RITA, salbutamol,
salinosporamide A, salmeterol, saxitoxin, Scopolamine, SH5, SH23,
SH24, SH25, shepherdin, SLF-CR, SM102-SM130, SMAC/DIABLO,
sorafenib, SP4206, Sparsomycin, Sphingomyelin, SQ22536, STATTIC,
Ste-MPKKKPTPIQLNP-NH.sub.2 (SEQ ID NO: 1), streptogramins,
suberoylanilide hydroxamic acid, substituted
3-(2-indolyl)piperidines, sunitinib, survivin, Tamoxifen,
tautomycin, temsirolimus, terbutaline, tetracyclins,
tetra-ubiquitin, tetrodotoxin, TGFa, TIJIP, TNFR,
trans-4-Iodo,4'-boranyl-chalcone, trichostatin A, tri-ubiquitin,
tubulin, U0126, Variolin, veratridine, VPPPVPPRRR (SEQ ID NO: 9),
ZD9331, Zeranol, Z-VAD(OMe)-FMK, Z-VAD-CHO, .omega.-agatoxins, and
.omega.-conotoxin.
Description
BACKGROUND
Current drug design and drug therapies have not addressed the
urgent need for therapies that interact with extended areas or
multiple domains of biomolecules such as proteins. For example,
there is an urgent need for therapies that are capable of, e.g.,
modulating protein-protein interactions, e.g., by interacting,
simultaneously with multiple domains on a single protein, or a
domain on one protein along with a domain on another protein. There
is also an urgent need for such therapies that modulate fusion
proteins, such as those that occur in cancer.
For example, signaling pathways are used by cells to generate
biological responses to external or internal stimuli. A few
thousand gene products control both ontogeny/development of higher
organisms and sophisticated behavior by their many different cell
types. These gene products can work in different combinations to
achieve their goals and often do so through protein-protein
interactions. Such proteins possess modular protein domains that
recognize, bind, and/or modify certain motifs. Protein-protein and
protein-nucleic acid recognition often function through protein
interactions domains, for example, such as the SH2, SH3, and PDZ
domains. These protein-interaction domains may represent a
meaningful area for developing targeted therapies. Other
macromolecular interactions that may serve as potential targets for
effective therapies include protein-nucleic acid interactions,
protein-carbohydrate interactions, and protein-lipid
interactions.
Current drug design and drug therapy approaches do not address this
urgent need to find drugs that interfere with intracellular
protein-protein interactions or protein signaling. Although
antibodies and other biological therapeutic agents may have
sufficient specificity to distinguish among closely related protein
surfaces, factors such as their high molecular weight prevent oral
administration and uptake of the antibodies. Conversely, orally
active pharmaceuticals are generally too small to disrupt
protein-protein surface interactions, which can be much larger than
the orally active pharmaceuticals. Further, previous attempts to
link, e.g., two pharmacophores that each interact with e.g.
different protein domains have focused on large covalently linked
compounds assembled in organic solvents. These assemblies typically
have a molecular weight too large for oral administration or
effective cellular and tissue permeation.
SUMMARY
Described herein are monomers capable of forming a biologically
useful multimer when in contact with one, two, three or more other
monomers in an aqueous media. In one aspect, such monomers may be
capable of binding to another monomer in an aqueous media (e.g. in
vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may
include a ligand moiety (e.g. a ligand or pharmacophore for the
target biomolecule), a linker element, and a connector element that
joins the ligand moiety and the linker element. In an aqueous
media, such contemplated monomers may join together via each linker
element and may thus be capable of modulating one or more
biomolecules substantially simultaneously, e.g., modulate two or
more binding domains on a protein or on different proteins.
In one aspect, a first silyl monomer capable of forming a
biologically useful multimer when in contact with one, two, three
or more second silyl monomers in an aqueous media is provided. The
first and second silyl monomer are represented by the formula:
X.sup.3--Y.sup.3--Z.sup.3 (Formula III) and pharmaceutically
acceptable salts, stereoisomers, metabolites and hydrates thereof,
wherein X.sup.3 is a first ligand moiety capable of binding to and
modulating a first target biomolecule; Y.sup.3 is absent or is a
connector moiety covalently bound to X.sup.3 and Z.sup.3; Z.sup.3
is independently selected from the group consisting of:
##STR00001## wherein
R.sup.W is selected from the group consisting of a bond,
--C.sub.1-4alkyl-, --O--C.sub.1-4alkyl-,
--N(R.sup.a)--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)C.sub.1-4alkyl-, --C.sub.1-4alkyl-O--C(O)--,
--C(O)--O--C.sub.1-4alkyl-, --NR.sup.a--C(O)--,
--C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-, --C.sub.3-6cycloalkyl-,
-phenyl-, -heteroaryl-, and -heterocyclic-; wherein C.sub.1-4alkyl,
R.sup.a, R.sup.b, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, heteroaryl, R.sup.a and R.sup.b, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic;
Q' is independently selected, for each occurrence, from the group
consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen, C.sub.1-4alkyl,
--O--C.sub.1-4alkyl and --NH--C.sub.1-4alkyl; wherein
C.sub.1-4alkyl may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
one or more additional heteroatoms selected from O, S, or N;
wherein the 4-7 membered heterocyclic ring may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo, amino and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
BB, independently for each occurrence, is a 4-7-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally
substituted with one, two, three or more groups represented by
R.sup.BB; wherein R.sup.1, independently for each occurrence, may
be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system; and
##STR00002##
wherein
Q.sup.2A is selected from the group consisting of a bond,
--O--C.sub.1-6alkyl-, --N(R')--C.sub.1-6alkyl-, and
--S--C.sub.1-6alkyl-;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-C(O)--, --C(O)C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR'--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, and -heteroaryl-; wherein
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', R.sup.a phenyl and heteroaryl may be
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl, halogen, hydroxyl,
nitro, carbamate, carbonate and cyano;
W.sup.1A, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--, --C.sub.1-4alkyl-N(R.sup.a)--,
--C.sub.1-4alkyl-C(O)--, --C(O)C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--C(O)--NR'--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, and -heteroaryl-; wherein
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', R.sup.a phenyl and heteroaryl may be
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl, halogen, hydroxyl,
nitro, carbamate, carbonate and cyano;
R' is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic;
Q.sup.1 and Q.sup.1A are independently selected, for each
occurrence, from the group consisting of --NHR', --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
W.sup.2A is CR.sup.W2A.
R.sup.W2A is selected from the group consisting of hydrogen,
C.sub.1-4alkyl, --O--C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, phenyl and heteroaryl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted independently, for each occurrence, with one, two,
three or more substituents selected from the group consisting of
halogen, hydroxyl and cyano;
BB, independently for each occurrence, is a 4-7-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety may be
optionally substituted with one, two, three or more groups
represented by R.sup.BB; wherein R.sup.1, independently for each
occurrence, may be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-14alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached may form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system.
In another aspect, a therapeutic multimer compound formed from the
multimerization in an aqueous media of a first monomer
X.sup.3--Y.sup.3--Z.sup.3 with a second monomer
X.sup.3--Y.sup.3--Z.sup.3 is provided.
In yet another aspect, a method of treating a disease associated
with a target protein or a target protein-protein interaction in a
patient in need thereof is provided. The method comprises
administering to the patient the monomer selected from
X.sup.3--Y.sup.3--Z.sup.3 (Formula IV), wherein upon
administration, the silyl monomer forms a homomultimer in vivo that
binds to one, two, three or more protein domains in said target
protein, or to at least one protein domain in each of the proteins
involved in the protein-protein interaction.
In still another aspect, a first monomer capable of forming a
biologically useful multimer when in contact with one, two, three
or more second monomers in an aqueous media is provided. The first
monomer is represented by the formula: X.sup.1--Y.sup.1--Z.sup.1
(Formula I)
and pharmaceutically acceptable salts, stereoisomers, metabolites
and hydrates thereof, wherein
X.sup.1 is a first ligand moiety capable of binding to and
modulating a first target biomolecule;
Y.sup.1 is absent or is a connector moiety covalently bound to
X.sup.1 and Z.sup.1;
Z.sup.1 comprises one, two, three or more silyl moieties; and
the second monomer comprises one, two, three or more silyl
moieties, capable of binding with the Z.sup.1 moiety of Formula I
to form the multimer.
In another aspect, a method of administering a pharmaceutically
effective amount of a multimeric compound to a patient in need
thereof is provided. The method comprises administering to the
patient thereof an amount of the first monomer and an amount of the
second monomer in amounts effective such that the pharmaceutically
effective amount of the resulting multimer is formed in vivo.
In yet another aspect, a therapeutic multimer compound formed from
the multimerization in an aqueous media of the first and second
monomer is provided. The first monomer is represented by:
X.sup.1--Y.sup.1--Z.sup.1 (Formula I)
and pharmaceutically acceptable salts, stereoisomers, metabolites
and hydrates thereof,
and the second monomer represented by: X.sup.2--Y.sup.2--Z.sup.2
(Formula II)
and pharmaceutically acceptable salts, stereoisomers, metabolites
and hydrates thereof.
In still another aspect, a method of modulating two or more target
biomolecule domains substantially simultaneously is provided. The
method comprises contacting an aqueous composition comprising said
target biomolecule domains with a first monomer represented by:
X.sup.1--Y.sup.1--Z.sup.1 (Formula I)
and pharmaceutically acceptable salts, stereoisomers, metabolites
and hydrates thereof, wherein X.sup.1 is a first ligand moiety
capable of binding to and modulating a first target biomolecule
domain; and a second monomer represented by:
X.sup.2--Y.sup.2--Z.sup.2 (Formula II), wherein X.sup.2 is a ligand
moiety capable of binding to and modulating a second target
biomolecule domain;
wherein upon contact with the aqueous composition, said first
monomer and said second monomer forms a multimer that binds to the
first target biomolecule domain and the second target biomolecule
domain.
In yet another aspect, a method of treating a disease associated
with two or more target biomolecule domains in a patient in need
thereof is provided. The method comprises administering to said
patient a first monomer represented by: X.sup.1--Y.sup.1--Z.sup.1
(Formula I) and pharmaceutically acceptable salts, stereoisomers,
metabolites and hydrates thereof, wherein X.sup.1 is a first ligand
moiety capable of binding to and modulating a first target
biomolecule domain; and
administering to said patient a second monomer represented by:
X.sup.2--Y.sup.2--Z.sup.2 (Formula II), wherein
X.sup.2 is a second ligand moiety capable of binding to a second
target biomolecule domain, wherein upon administration, said first
monomer and said second monomer forms a multimer in vivo that binds
to the first target biomolecule domain and the second target
biomolecule domain.
In still another aspect, a compound is selected from the group
consisting of:
(4-(3-(aminomethyl)phenyl)piperidin-1-yl)(4-((hydroxydimethylsilyl)me-
thoxy)-phenyl)methanone;
N-(4-(4-(3-(aminomethyl)phenyl)-piperidine-1-carbonyl)-2-chlorophenyl)-2--
(hydroxydimethylsilyl)acetamide;
N-(3-(4-(3-(aminomethyl)phenyl)piperidine-1-carbonyl)-phenyl)-2-(hydroxyd-
imethylsilyl)acetamide;
(4-(3-(aminomethyl)phenyl)piperidin-1-yl)(3-chloro-4-((hydroxydimethylsil-
yl)methoxy)-phenyl)methanone;
(4-(3-(aminomethyl)phenyl)-piperidin-1-yl)(3-((hydroxydimethylsilyl)-meth-
oxy)phenyl)methanone;
(4-(3-(aminomethyl)-phenyl)piperidin-1-yl)(3-chloro-5-((hydroxydimethylsi-
lyl)methoxy)phenyl)methanone;
N-(4-(4-(3-(aminomethyl)phenyl)-piperidine-1-carbonyl)phenyl)-2-(hydroxyd-
imethylsilyl)acetamide; and pharmaceutically acceptable salts,
stereoisomers, metabolites and hydrates thereof.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1A shows an x-ray co-crystal structure of a silyl multimer
bound to adjacent subunits of mast cell beta-tryptase-II, according
to an embodiment. The cationic aminomethyl-phenyl-piperidine
moieties of the multimer are bound in the pharmacophoric pockets of
the tryptase subunits, and the coferon monomers are joined by a
covalent disiloxane linkage;
FIG. 1B shows the chemical structure of the multimer bound to
tryptase in FIG. 1A, according to an embodiment;
FIG. 2 shows a reaction scheme for the formation of the 1:1
multimer, T46 homodimer (see FIG. 1A and FIG. 1B), from two T46
monomers, according to an embodiment;
FIG. 3A shows an x-ray co-crystal structure of T148 Homodimer bound
to adjacent subunits of mast cell beta-tryptase-II, according to an
embodiment. The cationic aminomethyl-phenyl-piperidine moieties of
the multimer are bound in the pharmacophoric pockets of the
tryptase subunits, and the coferon monomers are joined by a
covalent disiloxane linkage;
FIG. 3B shows the chemical structure of the homodimeric T148 bound
to tryptase in FIG. 3A, according to an embodiment; and
FIG. 4 shows a reaction scheme for the formation of the 1:1
multimer, T148 homodimer (right; see FIG. 3A and FIG. 3B), from two
T148 silanol monomers (left), according to an embodiment.
DETAILED DESCRIPTION
Described herein are monomers capable of forming a biologically
useful multimer when in contact with one, two, three or more other
monomers in an aqueous media. In one aspect, such monomers may be
capable of binding to another monomer in an aqueous media (e.g. in
vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may
include a ligand moiety (e.g. a ligand or pharmacophore moiety), a
linker element, and a connector element that joins the ligand
moiety and the linker element. In an aqueous media, such
contemplated monomers may join together via each linker element and
may thus be capable of modulating one or more biomolecules
substantially simultaneously, e.g., modulate two or more binding
domains on a protein or on different proteins. For example,
contemplated monomers may be separate or separatable in a solid or
in an aqueous media under one set of conditions, and when placed in
an aqueous media having one or more biomolecules, with another
(e.g., under a different set of conditions), can 1) form a multimer
through the linker on each monomer; and either: 2a) bind to the
biomolecule in two or more locations (e.g. protein domains) through
each ligand moiety of the respective monomer or 2b) bind to two or
more biomolecules through each ligand moiety of the respective
monomer. In an exemplary embodiment, disclosed monomers may
interact with another appropriate monomer (i.e. a monomeric pair)
in an aqueous media (e.g., in vivo) to form a multimer (e.g. a
dimer) that can bind to two separate target biomolecule domains
(e.g. protein domains).
The ligand moiety of a contemplated monomer, in some cases, may be
a pharmacophore or a ligand moiety that is e.g., capable of binding
to a biomolecule, such as for example, a protein, e.g. a specific
protein domain, a component of a biological cell such as ribosome
(composed of proteins and nucleic acids), or an enzyme active site
(e.g. a protease, such as tryptase). In some embodiments, the
linker element comprises a functional group capable of forming a
chemical bond with another linker element. In some embodiments, the
linker moiety may also serve as a signaling entity or "reporter,"
and in some instances the assembly of two or more linkers can
produce a fluorescent entity or fluorophore with properties
distinct from the individual linker moiety. In another aspect, a
plurality of monomers, each comprising a linker element, may react
to form a multimer connected by the linker elements. In some
embodiments, the multimer may be formedin vivo. In some instances,
the multimer may have enhanced properties relative to the monomers
that form the multimer. For example, in certain embodiments, the
multimer may bind to a target with greater affinity than any of the
monomers that form the multimer. Also described are methods of
making the compositions and methods of administering the
compositions.
In some embodiments, a plurality of monomers may assemble to form a
multimer. The multimer may be used for a variety of purposes. For
example, in some instances, the multimer may be used to perturb a
biological system. As described in more detail below, in some
embodiments, the multimer may bind to a target biomolecule, such as
a protein, nucleic acid, or polysaccharide. In certain embodiments,
the multimer may be used as a pharmaceutical.
Advantageously, in some embodiments, the multimer may form in vivo
upon administration of suitable monomers to a subject. Also
advantageously, the multimer may be capable of interacting with a
relatively large target site as compared to the individual monomers
that form the multimer. For example, a target may comprise, in some
embodiments, two protein domains separated by a distance such that
a multimer, but not a monomer, may be capable of binding to both
domains essentially simultaneously. In some embodiments,
contemplated multimers may bind to a target with greater affinity
as compared to a monomer binding affinity alone.
In some embodiments, a contemplated multimer may advantageously
exhibit enhanced properties relative to the monomers that form the
multimer. As discussed above, a multimer may have improved binding
properties as compared to the monomers alone. In some embodiments,
a multimer may have improved signaling properties. For example, in
some cases, the fluorescent properties of a multimer may be
different as compared to a monomer. As discussed in more detail
below, in some embodiments the fluorescent brightness of a multimer
at a particular wavelength may be greater than the fluorescent
brightness at the same wavelength of the monomers that form the
multimer. Advantageously, in some embodiments, a difference in
signaling properties between the multimer and the monomers that
form the multimer may be used to detect formation of the multimer.
In some embodiments, detection of the formation of the multimer may
be used to screen monomers, as discussed in more detail below. Also
as discussed in more detail below, in some embodiments, the
multimers may be used for imaging or as diagnostic agents.
It should be understood that a multimer, as used herein, may be a
homomultimer (i.e., a multimer formed from two or more essentially
identical monomers) or may be a heteromultimer (i.e., a multimer
formed from two or more substantially different monomers). In some
embodiments, a contemplated multimer may comprise 2 to about 10
monomers, for example, a multimer may be a dimer, a trimer, a
tetramer, or a pentamer.
In some embodiments, a monomer may comprise a ligand moiety, a
linker element, and a connector element that associates the ligand
moiety with the linker element. In some embodiments, the linker
element of a first monomer may combine with the linker element of a
second monomer. In some cases, the linker element may comprise a
functional group that can react with a functional group of another
linker element to form a bond linking the monomers. In some
embodiments, the linker element of a first monomer may be
substantially the same as the linker element of a second monomer.
In some embodiments, the linker element of a first monomer may be
substantially different than the linker element of a second
monomer.
In some cases, the ligand moiety may be a pharmacophore. In some
embodiments, the ligand moiety (e.g., a pharmacophore) may bind to
a target molecule with a dissociation constant of less than 1 mM,
in some embodiments less than 500 microM, in some embodiments less
than 300 microM, in some embodiments less than 100 microM, in some
embodiments less than 10 microM, in some embodiments less than 1
microM, in some embodiments less than 100 nM, in some embodiments
less than 10 nM, and in some embodiments less than 1 nM.
In some embodiments, the IC.sub.50 of the first monomer against a
first target biomolecule and the IC.sub.50 of the second monomer
against a second target biomolecule (or second binding site on the
first biomolecule) may be greater than the apparent IC.sub.50 of a
combination of the monomers against the first target biomolecule
and the second target biomolecule (or second binding site on the
first biomolecule). That is, the apparent IC.sub.50 of a
combination of the monomers against the first target biomolecule
and the second target biomolecule may advantageously be lower than
the IC.sub.50 of the first monomer against a first target
biomolecule and the IC.sub.50 of the second monomer against a
second target biomolecule. The combination of monomers may be any
suitable ratio. For example, the ratio of the first monomer to the
second monomer may be between 10:1 to 1:10, in some embodiments
between 5:1 and 1:5, and in some embodiments between 2:1 and 1:2.
In some cases, the ratio of the first monomer to the second monomer
may be essentially 1:1. In some instances, the ratio of the smaller
of the IC.sub.50 of the first monomer and the second monomer to the
apparent IC.sub.50 of the multimer may be at least 3.0. In other
instances, the ratio of the smaller IC.sub.50 of the first monomer
or the second monomer to the apparent IC.sub.50 of the multimer may
be at least 10.0. In some embodiments, the ratio of the smaller
IC.sub.50 of the first monomer or the second monomer to the
apparent IC.sub.50 of the multimer may be at least 30.0.
For example, for disclosed monomers forming a heteromultimer, the
apparent IC.sub.50 resulting from an essentially equimolar
combination of monomers against the first target biomolecule and
the second target biomolecule is at least about 3 to 10 fold lower,
at least about 10 to 30 fold lower, at least about 30 fold lower,
or at least about 40 to 50 fold lower than the lowest of the
IC.sub.50 of the second monomer against the second target
biomolecule or the IC.sub.50 of the first monomer against the first
target biomolecule.
It will be appreciated that for monomers forming homodimers (or
homo-oligomeric or homomultimeric, as described below), in aqueous
solution, there may an equilibrium between the monomeric and
dimeric (or oligomeric) states with higher concentrations favoring
greater extent of dimer formation. As the binding of monomers to
the target biomolecule increases their proximity and effectively
increases their local concentration on the target, the rate and
extent of dimerization (oligomerization) is promoted when
geometries are favorable. As a result, the occupancy of the target
by favorable monomers may be nearly completely in the homodimeric
(or oligomeric) state. In this manner the target for example, may
serve as a template for the dimerization of the monomers,
significantly enhancing the extent and rate of dimerization.
Affinities of heterodimerizing monomers for the target
biomolecule(s) can often be assessed through the testing of the
respective monomers in appropriate assays for the target activity
or biology because their self-association to form homo-dimers may
not be promoted by binding to the target(s). In contrast, the
testing of homodimerizing monomers may not, in some embodiments,
afford an affinity solely for the monomeric or dimeric state, but
rather the observed effect (e.g. IC.sub.50) is a result of the
monomer-dimer dynamics and equilibrium, with the apparent binding
affinity (or IC.sub.50) being e.g., a weighted measure of the
monomer and dimeric inhibitory effects upon the target. In some
embodiments, a dimeric species may not form in detectable
concentrations in solution, yet a target biomolecule may be bound
primarily by the dimeric species, indicating that a dimeric species
does in fact form. Thus, the ability or lack of ability to detect a
dimeric species in solution should not be construed as an
indication of whether dimeric species is being formed.
In some cases, the pH of the aqueous fluid in which the multimer
forms may be between pH 1 and and 9, in some embodiments between pH
1 and 3, in some embodiments between pH 3 and 5, in some
embodiments between pH 5 and 7, and in some embodiments between pH
7 and 9. In some embodiments, the multimer may be stable in an
aqueous solution having a pH between pH 1 and 9, in some
embodiments between pH 1 and 3, in some embodiments between pH 3
and 5, in some embodiments between pH 5 and 7, and in some
embodiments between pH 7 and 9. In some embodiments, the aqueous
solution may have a physiologically acceptable pH.
In some embodiments, the ligand moiety may be capable of binding to
a target and at least partially disrupting a
biomolecule-biomolecule interaction (e.g., a protein-protein
interaction). In some embodiments, the ligand moiety may be capable
of binding to a target and at least partially disrupting a
protein-nucleic acid interaction. In some cases, the ligand moiety
may be capable of binding to a target and at least partially
disrupting a protein-lipid interaction. In some cases, the ligand
moiety may be capable of binding to a target and at least partially
disrupting a protein-polysaccharide interaction. In some
embodiments, the ligand moiety may be capable of at least partially
stabilizing a biomolecule-biomolecule interaction. In certain
embodiments, the ligand moiety may be capable of at least partially
inhibiting a conformational change in a biomolecule target.
In some instances, the linker element may be capable of generating
a signal. For example, in some embodiments, the linker element may
be capable of fluorescing. In some cases, the linker element may
have greater fluorescence when the monomer to which it is attached
is part of a multimer as compared to when the monomer to which it
is attached is not part of a multimer. In some embodiments, upon
multimer formation, the fluorescent brightness of a linker element
may increase by at least 2-fold, in some embodiments by at least
5-fold, in some embodiments by at least 10-fold, in some
embodiments by at least 50-fold, in some embodiments by at least
100-fold, in some embodiments by at least 1000-fold, and in some
embodiments by at least 10000-fold. In some embodiments, a linker
element in a multimer may have a peak fluorescence that is
red-shifted relative to the peak fluorescence of the linker element
in a monomer. In other embodiments, a linker element may have a
peak fluorescence that is blue-shifted relative to the peak
fluorescence of a linker element in a monomer.
Monomers
In a certain embodiment, a first silyl monomer may be capable of
forming a biologically useful multimer when in contact with one,
two, three or more second silyl monomers. The first and second
silyl monomer are represented by the formula:
X.sup.3--Y.sup.3--Z.sup.3 (Formula III) and pharmaceutically
acceptable salts, stereoisomers, metabolites and hydrates thereof,
wherein X.sup.3 is a first ligand moiety capable of binding to and
modulating a first target biomolecule; Y.sup.3 is absent or is a
connector moiety covalently bound to X.sup.3 and Z.sup.3; Z.sup.3
is independently selected from the group consisting of:
##STR00003##
wherein
R.sup.W is selected from the group consisting of a bond,
--C.sub.1-4alkyl-, --O--C.sub.1-4alkyl-,
--N(R.sup.a)--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)C.sub.1-4alkyl-, --C.sub.1-4alkyl-O--C(O)--,
--C(O)--O--C.sub.1-4alkyl-, --NR.sup.a--C(O)--,
--C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-, --C.sub.3-6cycloalkyl-,
-phenyl-, -heteroaryl-, and -heterocyclic-; wherein C.sub.1-4alkyl,
R.sup.a, R.sup.b, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, heteroaryl, R.sup.a and R.sup.b, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' may be independently selected, for each occurrence, from the
group consisting of hydrogen, substituted or unsubstituted
aliphatic, and substituted or unsubstituted heteroaliphatic;
Q.sup.1 may be independently selected, for each occurrence, from
the group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b may be independently selected, for each
occurrence, from the group consisting of hydrogen, C.sub.1-4alkyl,
--O--C.sub.1-4alkyl and --NH--C.sub.1-4alkyl; wherein
C.sub.1-4alkyl may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
one or more additional heteroatoms selected from O, S, or N;
wherein the 4-7 membered heterocyclic ring may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo, amino and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
BB, independently for each occurrence, may be a 4-7-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally
substituted with one, two, three or more groups represented by
R.sup.BB; wherein R.sup.1, independently for each occurrence, may
be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system; and
##STR00004##
wherein
Q.sup.2A may be selected from the group consisting of a bond,
--O--C.sub.1-6alkyl-, --N(R')--C.sub.1-6alkyl-, and
--S--C.sub.1-6alkyl-;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-C(O)--, --C(O)C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR'--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, and -heteroaryl-; wherein
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', R.sup.a phenyl and heteroaryl may be
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl, halogen, hydroxyl,
nitro, carbamate, carbonate and cyano;
W.sup.1A, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--, --C.sub.1-4alkyl-N(R.sup.a)--,
--C.sub.1-4alkyl-C(O)--, --C(O)C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--C(O)--NR'--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, and -heteroaryl-; wherein
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', R.sup.a phenyl and heteroaryl may be
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl, halogen, hydroxyl,
nitro, carbamate, carbonate and cyano;
R' may be independently selected, for each occurrence, from the
group consisting of hydrogen, substituted or unsubstituted
aliphatic, and substituted or unsubstituted heteroaliphatic;
Q.sup.1 and Q.sup.1A may be independently selected, for each
occurrence, from the group consisting of --NHR', --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b may be independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
W.sup.2A may be CR.sup.W2A.
R.sup.W2A may be selected from the group consisting of hydrogen,
C.sub.1-4alkyl, --O--C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, phenyl and heteroaryl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted independently, for each occurrence, with one, two,
three or more substituents selected from the group consisting of
halogen, hydroxyl and cyano;
BB, independently for each occurrence, may be a 4-7-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety may be
optionally substituted with one, two, three or more groups
represented by R.sup.BB; wherein R.sup.1, independently for each
occurrence, may be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system;
R.sup.W is selected from the group consisting of a bond,
--C.sub.1-4alkyl-, --O--C.sub.1-4alkyl-,
--N(R.sup.a)--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)C.sub.1-4alkyl-, --C.sub.1-4alkyl-O--C(O)--,
--C(O)--O--C.sub.1-4alkyl-, --NR.sup.a--C(O)--,
--C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-, --C.sub.3-6cycloalkyl-,
-phenyl-, -heteroaryl-, and -heterocyclic-; wherein C.sub.1-4alkyl,
R.sup.a, R.sup.b, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, heteroaryl, R.sup.a and R.sup.b, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino.
It should be noted that substituents R.sup.w, Q.sup.2A, W.sup.1,
and W.sup.1A are oriented such that a Si-heteroatom bond does not
occur (e.g., a Si--O bond, a Si--N bond, or a Si--S bond). For
example, when R.sup.w is --O--C.sub.1-4alkyl-, the
--O--C.sub.1-4alkyl-substituent would be oriented such that Si is
bonded to the C.sub.1-4alkyl group (e.g., --O--C.sub.1-4alkyl-Si--)
and not to the O atom.
In some cases, the first silyl monomer may form a biologically
useful multimer when in contact with one, two, three or more second
silyl monomers in vivo. For example, the multimer may be a
biologically useful dimer when the first silyl monomer is in
contact with the second silyl monomer. Alternatively, the multimer
may be a biologically useful trimer when the first silyl monomer is
in contact with two second silyl monomers. In other instances, the
multimer may be a biologically useful cyclic tetramer when the
first silyl monomer is in contact with three second silyl
monomers.
In some embodiments, the ligand moiety may be a pharmacophore and
the target biomolecule may be a protein target. For example, the
first target biomolecule may be a protein component of the
ribosome. In another embodiment, the first target biomolecule may
be a subunit of tryptase. In other cases, X.sup.3 may be a
non-peptidyl ligand moiety.
In another embodiment, the modulating effects of the multimer
formed from the silyl monomers is greater than the sum of the
modulating effects of the individual monomers.
In certain embodiments, a first monomer may be capable of forming a
biologically useful multimer when in contact with one, two, three
or more second monomers in an aqueous media, wherein the first
monomer is represented by the formula: X.sup.1--Y.sup.1--Z.sup.1
(Formula I)
and pharmaceutically acceptable salts, stereoisomers, metabolites
and hydrates thereof, wherein X.sup.1 is a first ligand moiety
capable of binding to and modulating a first target biomolecule;
Y.sup.1 is absent or is a connector moiety covalently bound to
X.sup.1 and Z.sup.1; Z.sup.1 comprises one, two, three or more
silyl moieties; and
the second monomer comprises one, two, three or more silyl
moieties, capable of binding with the Z.sup.1 moiety of Formula I
to form the multimer.
In some instances, Z.sup.1 may further comprise a diol moiety.
Additionally, the second monomer may further comprise a boronic
acid or oxaborale moiety, which may be capable of binding with the
Z.sup.1 moiety.
In some embodiments, Z.sup.1 may be independently selected, for
each occurrence, from the group consisting of:
##STR00005##
wherein
A.sup.1 is (a) absent; or (b) selected from the group consisting of
acyl, substituted or unsubstituted aliphatic, and substituted or
unsubstituted heteroaliphatic;
A.sup.2, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --N--, acyl, substituted or
unsubstituted aliphatic, and substituted or unsubstituted
heteroaliphatic, provided that at least one of A.sup.1 and A.sup.2
is present; or
A.sup.1 and A.sup.2, together with the atoms to which they are
attached, form a 4-8 membered cycloalkyl or heterocyclic ring;
A.sup.3 is selected from the group consisting of --NHR', --SH, and
--OH;
W.sup.2 is selected from the group consisting of CR' or N;
m is 1-6;
represents a single or double bond; and
R.sup.X is (a) absent; or (b) selected from the group consisting of
hydrogen, substituted or unsubstituted aliphatic, and substituted
or unsubstituted heteroaliphatic;
Q.sup.2 is (a) absent; or (b) selected from the group consisting of
a substituted or unsubstituted aliphatic and a substituted or
unsubstituted heteroaliphatic moiety; or
R.sup.X and Q.sup.2 together with the atoms to which they are
attached form a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl or
heterocyclic ring;
Q.sup.3 is selected from the group consisting of a substituted or
unsubstituted aliphatic and a substituted or unsubstituted
heteroaliphatic moiety;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic;
Q.sup.1 is independently selected, for each occurrence, from the
group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
BB, independently for each occurrence, is a 5- or 6-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally
substituted with one, two, three or more groups represented by
R.sup.BB; wherein R.sup.1, independently for each occurrence, may
be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system; and
##STR00006##
wherein
A.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of acyl, substituted or
unsubstituted aliphatic, and substituted or unsubstituted
heteroaliphatic;
A.sup.3, independently for each occurrence, is selected from the
group consisting of --NHR', --N(R').sub.2, --SH, and --OH;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic;
Q.sup.1 is independently selected, for each occurrence, from the
group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
BB, independently for each occurrence, is a 5- or 6-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally
substituted with one, two, three or more groups represented by
R.sup.BB; wherein R.sup.1, independently for each occurrence, may
be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system; and
##STR00007##
wherein
A.sup.3, independently for each occurrence, is selected from the
group consisting of --NHR', --SH, and --OH;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, C.sub.1-4alkyl and phenyl; or R.sup.3 and R.sup.4
taken together form a 3-6 membered ring;
R.sup.5 and R.sup.6 are independently selected from the group
consisting of H, C.sub.1-4alkyl; wherein C.sub.1-4alkyl is
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of hydroxyl, amino, halo, thio, C.sub.1-4alkoxy,
halogen, --OH, --CN, --COOH, and C(O)--NHR''; or R.sub.5 and
R.sub.6, taken together form phenyl or a 4-6 membered
heterocycle;
R'' is selected from the group consisting of H and
C.sub.1-4alkyl;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic;
Q.sup.1 is independently selected, for each occurrence, from the
group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
AR is a fused phenyl or 4-7 membered aromatic or partially aromatic
heterocyclic ring; wherein AR is optionally substituted by oxo,
C.sub.1-4alkyl optionally substituted by hydroxyl, amino, halo, or
thio; C.sub.1-4alkoxy; --S-- C.sub.1-4alkyl; halogen; --OH; --CN;
--COOH; --CONHR'; wherein the two hydroxyl moieties are ortho to
each other; and
the carbons of the phenyl ring may be independently, for each
occurrence, optionally replaced by one or two nitrogens.
##STR00008##
wherein
W.sup.3, independently for each occurrence, is selected from the
group consisting of N and CR.sup.W3
R.sup.W3, independently for each occurrence, is selected from the
group consisting of hydrogen, C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, phenyl and
heteroaryl; wherein C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, phenyl and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of halogen, hydroxyl and cyano;
Q.sup.3 is selected from the group consisting of a bond,
--C.sub.1-4alkyl-, --C.sub.2-6alkenyl-, --C.sub.1-6cycloalkyl-, a
5-6 membered heterocyclic ring, and phenyl;
Q.sup.2, independently for each occurrence, is selected from the
group consisting of H, C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.1-6cycloalkyl, a 5-6 membered heterocyclic ring, phenyl,
substituted or unsubstituted aliphatic, substituted or
unsubstituted heteroaliphatic, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl;
A.sup.3, independently for each occurrence, is selected from the
group consisting of NH.sub.2, --SH, and --OH;
A.sup.4, independently for each occurrence, is selected from the
group consisting of --NH.sub.2, --NH--NH.sub.2; --NHOH, --NH--OR'',
--SH, and --OH;
R'' is selected from the group consisting of H and
C.sub.1-4alkyl;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic;
Q.sup.1 is independently selected, for each occurrence, from the
group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
BB, independently for each occurrence, is a 5- or 6-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally
substituted with one, two, three or more groups represented by
R.sup.BB; wherein R.sup.1, independently for each occurrence, may
be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system.
In a certain embodiment, the second monomer may be represented by:
X.sup.2--Y.sup.2--Z.sup.2 (Formula II), and pharmaceutically
acceptable salts, stereoisomers, metabolites and hydrates thereof,
wherein X.sup.2 is a second ligand moiety capable of binding to and
modulating a second target biomolecule; Y.sup.2 is absent or is a
connector moiety covalently bound to X.sup.2 and Z.sup.2; Z.sup.2
comprises one, two, three or more silyl moieties.
In another embodiment, Z.sup.2 may further comprise a boronic acid
or oxaborale moiety.
In certain embodiments, Z.sup.1 and Z.sup.2 may be independently
selected, for each occurrence, from the group consisting of:
##STR00009##
wherein
R.sup.W is selected from the group consisting of a bond,
--C.sub.1-4alkyl-, --O--C.sub.1-4alkyl-,
--N(R.sup.a)--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)C.sub.1-4alkyl-, --C.sub.1-4alkyl-O--C(O)--,
--C(O)--O--C.sub.1-4alkyl-, --NR.sup.a--C(O)--,
--C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-, --C.sub.3-6cycloalkyl-,
-phenyl-, -heteroaryl-, and -heterocyclic-; wherein C.sub.1-4alkyl,
R.sup.a, R.sup.b, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, heteroaryl, R.sup.a and R.sup.b, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' may be independently selected, for each occurrence, from the
group consisting of hydrogen, substituted or unsubstituted
aliphatic, and substituted or unsubstituted heteroaliphatic;
Q.sup.1 may be independently selected, for each occurrence, from
the group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b may be independently selected, for each
occurrence, from the group consisting of hydrogen, C.sub.1-4alkyl,
--O--C.sub.1-4alkyl and --NH--C.sub.1-4alkyl; wherein
C.sub.1-4alkyl may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
one or more additional heteroatoms selected from O, S, or N;
wherein the 4-7 membered heterocyclic ring may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo, amino and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3 6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
BB, independently for each occurrence, may be a 4-7-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety, wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety is optionally
substituted with one, two, three or more groups represented by
R.sup.BB; wherein R.sup.1, independently for each occurrence, may
be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system; and
##STR00010##
wherein
Q.sup.2A may be selected from the group consisting of a bond,
--O--C.sub.1-6alkyl-, --N(R')--C.sub.1-6alkyl-, and
--S--C.sub.1-6alkyl-;
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-C(O)--, --C(O)C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR'--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, and -heteroaryl-; wherein
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', R.sup.a phenyl and heteroaryl may be
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl, halogen, hydroxyl,
nitro, carbamate, carbonate and cyano;
W.sup.1A, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--, --C.sub.1-4alkyl-N(R.sup.a)--,
--C.sub.1-4alkyl-C(O)--, --C(O)C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--C(O)--NR'--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, and -heteroaryl-; wherein
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', R.sup.a phenyl and heteroaryl may be
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl, halogen, hydroxyl,
nitro, carbamate, carbonate and cyano;
R' may be independently selected, for each occurrence, from the
group consisting of hydrogen, substituted or unsubstituted
aliphatic, and substituted or unsubstituted heteroaliphatic;
Q.sup.1 and Q.sup.1A may be independently selected, for each
occurrence, from the group consisting of --NHR', --N(R').sub.2,
--NR.sup.aR.sup.b, --O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR',
--SH, --OH, --O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl,
--S-aryl, heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b may be independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
W.sup.2A may be CR.sup.W2A.
R.sup.W2A may be selected from the group consisting of hydrogen,
C.sub.1-4alkyl, --O--C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, phenyl and heteroaryl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted independently, for each occurrence, with one, two,
three or more substituents selected from the group consisting of
halogen, hydroxyl and cyano;
BB, independently for each occurrence, may be a 4-7-membered
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein the
cycloalkyl, heterocyclic, aryl, or heteroaryl moiety may be
optionally substituted with one, two, three or more groups
represented by R.sup.BB; wherein R.sup.1, independently for each
occurrence, may be optionally bonded to BB;
each R.sup.BB is independently selected, for each occurrence, from
the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, substituted or unsubstituted heteroaliphatic (e.g.,
--C.sub.1-4alkyl, --O--C.sub.1-4alkyl,
--N(R.sup.a)--C.sub.1-4alkyl, --C(O)C.sub.1-4alkyl,
--C(O)--O--C.sub.1-4alkyl, --C(O)--NR.sup.aR.sup.b,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-6cycloalkyl),
heterocyclic, phenyl, phenoxy, heteroaryl,
--C.sub.1-4alkylene-phenyl, --C.sub.1-4alkylene-heteroaryl,
--C.sub.1-4alkylene-heterocyclyl, --C.sub.2-6alkenylene-phenyl,
--C.sub.2-6alkenylene-heteroaryl,
--C.sub.2-6alkenylene-heterocyclyl, --C.sub.2-6alkynyl-phenyl,
--C.sub.2-6alkynyl-heteroaryl, --C.sub.2-6alkynyl-heterocyclyl;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, phenyl and heteroaryl may be optionally
substituted by one, two, three or more substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
--C(O)C.sub.1-4alkyl, --C(O)--O--C.sub.1-4alkyl,
--C(O)--NR.sup.aR.sup.b, halogen, cyano, hydroxyl, cycloalkyl,
heterocyclic, phenyl, or heteroaryl, and R.sup.a and R.sup.b are
defined herein; or two R.sup.BB together with the atoms to which
they are attached form a fused 5- or 6-membered cycloalkyl or
heterocyclic bicyclic ring system.
In some embodiments, Z.sup.3, Z.sup.2, and Z.sup.1 may be
independently selected, for each occurrence, from Group A; wherein
W.sup.1 independently, for each occurrence, may be absent or
selected from the group consisting C.sub.1-4alkyl or phenyl;
wherein BB may be selected independently, for each occurrence, from
phenyl or heteroaryl; and wherein R.sup.1 and R.sup.2 may be
independently selected, for each occurrence, from methyl or --OH;
and wherein Q.sup.1 may be --OH. For example, R.sup.2 and Q.sup.1
may be --OH.
In other embodiments, Z.sup.3, Z.sup.2, and Z.sup.1 may be
independently selected, for each occurrence, from the group
consisting of:
##STR00011##
wherein
R.sup.BB is independently selected, for each occurrence, from the
group consisting of hydrogen, halogen, nitro, cyano, hydroxyl,
amino, thio, --COOH, --CONHR', substituted or unsubstituted
aliphatic, and substituted or unsubstituted heteroaliphatic;
W.sup.1, independently selected for each occurrence, is (a) absent
or (b) --C.sub.1-4 alkyl-;
Q.sup.1 is independently selected for each occurrence from the
group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.1 and R.sup.2, independently selected, for each occurrence,
may be C.sub.1-6alkyl.
In certain embodiments, Z.sup.3 Z.sup.2, and Z.sup.1 may be
independently selected, for each occurrence, from the group
consisting of:
##STR00012##
wherein
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl; and
m is 0, 1, 2, 3 or 4.
In another embodiment, Z.sup.3, Z.sup.2, and Z.sup.1 may be
independently selected, for each occurrence, from the group
consisting of:
##STR00013##
wherein
R.sup.1 and R.sup.2, independently selected, for each occurrence,
from the group consisting of C.sub.1-6alkyl and
C.sub.1-6alkoxy;
m is 0, 1, 2, 3 or 4;
R'' is selected from the group consisting of --C.sub.1-2alkyl-.
--O--C.sub.1-2alkyl-, and --NH(C.dbd.O)C.sub.1-2alkyl; wherein
C.sub.1-2alkyl is optionally substituted independently, for each
occurrence, with one, two, three or more fluorines.
In some embodiments, Z.sup.3, Z.sup.2, and Z.sup.1 may be
independently selected, for each occurrence, from Group B; wherein
W.sup.1 and W.sup.1A independently, for each occurrence, may be
absent or C.sub.1-4alkyl; and wherein BB may be selected
independently, for each occurrence, from phenyl or heteroaryl. For
example, W.sup.1 may be --C.sub.1-4alkyl- and W.sup.1A may be
absent. Alternatively, W.sup.1 and W.sup.1A may be
--C.sub.1-4alkyl-. In some embodiment, W.sup.1 and W.sup.1A may be
absent. For example BB may be selected from the group consisting
of
##STR00014##
In a certain embodiment, Z.sup.3, Z.sup.2, and Z may be
independently selected, for each occurrence, from the group
consisting of:
##STR00015##
wherein
W.sup.1 and W.sup.1A, independently selected, for each occurrence,
are (a) absent or (b) --C.sub.1-4alkyl-;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl; and
m is 0, 1, 2, 3 or 4.
In another embodiment, Z.sup.3, Z.sup.2, and Z.sup.1 may be
independently selected, for each occurrence, from the group
consisting of:
##STR00016##
wherein
W.sup.1 and W.sup.1A, independently selected, for each occurrence,
are (a) absent or (b) --C.sub.1-4alkyl-;
R.sup.1 and R.sup.2, independently selected, for each occurrence,
are selected from the group consisting of C.sub.1-6alkyl and
--O--C.sub.1-6alkyl.
In certain embodiments, Z.sup.2 may be independently selected, for
each occurrence, from the group consisting of:
##STR00017##
wherein
W.sup.1, independently for each occurrence, is (a) absent; or (b)
selected from the group consisting of --C.sub.1-4alkyl-,
--O--C.sub.1-4alkyl-, --C.sub.1-4alkyl-C(O)--,
--C(O)--C.sub.1-4alkyl-, --N(R.sup.a)--C.sub.1-4alkyl-,
--C.sub.1-4alkyl-O--C(O)--, --C(O)--O--C.sub.1-4alkyl-,
--NR.sup.a--C(O)--, --C.sub.2-6alkenyl-, --C.sub.2-6alkynyl-,
--C.sub.3-6cycloalkyl-, -phenyl-, -heteroaryl-, and heterocyclic;
wherein C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, R', phenyl, heterocyclic, and heteroaryl are
optionally substituted independently, for each occurrence, with
one, two, three or more substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-4alkoxy, --C(O)C.sub.1-6alkyl, --C(O)--O--C.sub.1-4alkyl,
cycloalkyl, heterocyclic, phenyl, heteroaryl, halogen, hydroxyl,
nitro sulfoxide, sulfone, sulfonamide and cyano, wherein the
cycloalkyl, heterocyclic, phenyl, or heteroaryl moiety is
optionally substituted with one, two, three or more substituents
selected from halogen, amino, cyano, hydroxyl, C.sub.1-6alkyl,
phenyl, heteroaryl, and amino;
R' is independently selected, for each occurrence, from the group
consisting of hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic;
Q.sup.1 is independently selected, for each occurrence, from the
group consisting of --NHR', --N(R').sub.2, --NR.sup.aR.sup.b,
--O--Si(R').sub.3, --O--SiR.sup.aR.sup.bR', --SH, --OH,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, --O-aryl, --S-aryl,
heteroaryl, --O-heteroaryl, --S-heteroaryl, halogen and
--O--C.sub.1-6alkyl-NR.sup.aR.sup.b;
R.sup.a and R.sup.b are independently selected, for each
occurrence, from the group consisting of hydrogen and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl may be optionally
substituted by one or more substituents selected from the group
consisting of halogen, cyano, oxo and hydroxyl; or
R.sup.a and R.sup.b, together with the nitrogen to which they are
attached, may form a 4-7 membered heterocyclic ring, which may have
an additional heteroatom selected from O, S, or N; wherein the 4-7
membered heterocyclic ring may be optionally substituted by one or
more substituents selected from the group consisting of halogen,
cyano, oxo and hydroxyl;
R.sup.1 and R.sup.2 are selected independently, for each
occurrence, from the group consisting of --OH, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
--C.sub.1-6alkyl-NR.sup.aR.sup.b, phenyl and heteroaryl; wherein
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, R.sup.a,
R.sup.b, phenyl and heteroaryl, independently selected, for each
occurrence, may be optionally substituted by one or more
substituents selected from the group consisting of halogen, cyano,
hydroxyl, amino, C.sub.1-6alkyl, heteroaryl, and phenyl; or R.sup.1
and R.sup.2, together with the silicon to which they are attached,
may form a 5-8 membered heterocyclic ring, which may have one or
more additional heteroatoms selected from O, S, or N; wherein the
5-8 membered heterocyclic ring may be optionally substituted by one
or more substituents selected from the group consisting of halogen,
cyano, oxo, amino and hydroxyl;
R.sup.8, independently for each occurrence, is selected from the
group consisting of H, halogen, oxo and C.sub.1-4alkyl; wherein
C.sub.1-4alkyl is optionally substituted by one or more
substituents selected from the group consisting of hydroxyl, amino,
halo, thio. C.sub.2-4alkenyl, C.sub.1-4alkoxy, --S--
C.sub.1-4alkyl, --CN, --COOH and --C(O)--NHR'';
AA, independently for each occurrence, is a 5-7 membered
heterocyclic ring having one, two, or three heteroatoms, or phenyl;
wherein AA is optionally substituted by one, two, or three
substituents selected from the group consisting of halo and
C.sub.1-4alkyl; wherein C.sub.1-4alkyl is optionally substituted by
one or more substituents selected from the group consisting of
hydroxyl, amino, halo, thio. C.sub.2-4alkenyl, C.sub.1-4alkoxy,
--S-- C.sub.1-4alkyl, --CN, --COOH and --C(O)--NHR'', or two
substituents together with the atoms to which they are attached
form a fused 5- or 6-membered cycloalkyl or heterocyclic bicyclic
ring system; and
R'' is selected independently, for each occurrence, from the group
consisting of H and C.sub.1-4alkyl.
In some cases, the first monomer may form a biologically useful
multimer when in contact with one, two, three or more second
monomers in vivo. For example, the multimer may be a biologically
useful dimer when the first monomer is in contact with the second
monomer. Alternatively, the multimer may be a biologically useful
trimer when the first monomer is in contact with two second
monomers. In other instances, the multimer may be a biologically
useful cyclic tetramer when the first monomer is in contact with
three second monomers.
As discussed above, the ligand moiety may be a pharmacophore and
the target biomolecule may be a protein target. In some cases, the
first target biomolecule and the second target biomolecule may be
the same. In other cases, the first target biomolecule and the
second target biomolecule may be different. For example, the first
target biomolecule may be a ribosome. In another embodiment, the
first target biomolecule may be a tryptase. Alternatively, the
second target biomolecule may be a ribosome. In another embodiment,
the second target biomolecule may be a tryptase.
In other cases, X.sup.1 may be a non-peptidyl ligand moiety. In
some instances, X.sup.2 may be a non-peptidyl ligand moiety. In one
embodiment, X.sup.1 and X.sup.2 may be the same. In another
embodiment, X.sup.1 and X.sup.2 may be the different.
In some embodiments, the effects of the multimer formed from the
monomers may be greater than the sum of the effects of the
individual monomers. For example, the ratio of the smaller of the
apparent IC.sub.50 of the first monomer or the second monomer to
the apparent IC.sub.50 of the multimer may be at least 3.0, 10.0 or
30.0.
In certain embodiments, the first monomer and the second monomer
may reversibly associate to form the multimer.
As discussed above, a monomer may be capable of reacting with one
or more other monomers to form a multimer in an aqueous
composition, e.g. in vivo. In some embodiments, a first monomer may
react with a second monomer to form a dimer. In other embodiments,
a first monomer may react with two second monomers to form a
trimer. In still other embodiments, a first monomer may react with
three second monomers to form a cyclic tetramer. In some
embodiments, each of the monomers that form a multimer may be
essentially the same. In some embodiments, each of the monomers
that form a multimer may be substantially different. In certain
embodiments, at least some of the monomers that form a multimer may
be essentially the same or may be substantially different.
In some embodiments, the linker element of a first monomer and the
linker element of a second monomer may be substantially different.
In other embodiments, the connector element of a first monomer and
the connector element of a second monomer may be substantially
different. In still other embodiments, the ligand moiety (e.g.,
pharmacophore) of a first monomer and the ligand moiety (e.g.
pharmacophore) of the second monomer may be substantially
different.
In some cases, formation of a multimer from a plurality of monomers
may be irreversible. In some embodiments, formation of a multimer
from a plurality of monomers may be reversible. For example, in
some embodiments, the multimer may have an oligomer or dimer
dissociation constant between 10 mM and 1 nM, in some embodiments
between 1 mM and 100 nM, in some embodiments between 1 mM and 1
.mu.M, and in some embodiments between 500 mM and 1 .mu.M. In
certain embodiments, the multimer may have a dissociation constant
of less than 10 mM, in some embodiments less than 1 mM, in some
embodiments less than 500 .mu.M, in some embodiments less than 100
.mu.M, in some embodiments less than 50 .mu.M, in some embodiments
less than 1 .mu.M, in some embodiments less than 100 nM, and in
some embodiments less than 1 nM.
While the affinity of the multimer for its target biomolecule(s)
often cannot be measured directly due to the dynamic reversible
equilibrium with its monomers in an aqueous or biological milieu,
it may be possible to extract an apparent multimer-target
dissociation constant from a series of experimental determinations.
Exploring the effects of a matrix of monomer concentrations,
monomer ratios, along with changes in concentration(s) in the
target biomolecule(s), coupled with determinations of
multimer-monomer dissociation constants, and in some cases
additional binding competition, kinetic and biophysical methods,
one can extract an estimate of the affinity of the multimeric
assembly for its target(s). Through such approaches, one can
demonstrate that in some embodiments, the affinity of the multimer
for the target biomolecule(s) are less than 1 .mu.M, in some
embodiments less than 1 nM, in some embodiments less than 1 pM, in
some embodiments less than 1 fM, and in some embodiments less than
1 aM, and in some embodiments less than 1 zM.
Multimers
Without wishing to be bound by any theory, it is believed that
molecular self-assembly may be directed through noncovalent
interactions, e.g., hydrogen bonding, metal coordination,
hydrophobic forces, van der Waals forces, pi-pi interactions,
electrostatic, and/or electromagnetic interactions.
Without wishing to be bound by any theory, pi-pi and pi-cation
interactions can be used to drive multimerization. In addition, van
der Waals and electromagnetic forces are other interactions that
can help to drive multimerization. Alternatively, acid/base pairs
and donor-acceptor pairs, e.g., amide and/or sulfonamide pairs, can
be employed to help direct self-assembly. In other cases, use of
hydrophobic interactions can be used for multimerization targeting
a membrane-bound protein. Additionally, metal coordination might be
used when the target itself incorporates the metal, but could also
be used in other scenarios.
In some embodiments, a first monomer and a second monomer may form
a dimer in aqueous solution. For example, in some instances, the
first monomer may form a biologically useful dimer with a second
monomer in vivo.
In another embodiment, a therapeutic multimer compound may form
from the multimerization in an aqueous media of a first monomer
X.sup.3--Y.sup.3--Z.sup.3 with a second monomer
X.sup.3--Y.sup.3--Z.sup.3.
In certain embodiments, a therapeutic multimer compound may form
from the multimerization in an aqueous media of the first monomer
represented by: X.sup.1--Y.sup.1--Z.sup.1 (Formula I),
and pharmaceutically acceptable salts, stereoisomers, metabolites
and hydrates thereof, and the second monomer represented by:
X.sup.2--Y.sup.2--Z.sup.2 (Formula II),
and pharmaceutically acceptable salts, stereoisomers, metabolites
and hydrates thereof.
For example, X.sup.1 is a first ligand moiety capable of binding to
and modulating a first target biomolecule; Y.sup.1 is absent or is
a connector moiety covalently bound to X.sup.1 and Z.sup.1; Z.sup.1
is independently selected from the groups discussed above; X.sup.2
is a second ligand moiety capable of binding to and modulating a
second target biomolecule; Y.sup.2 is absent or is a connector
moiety covalently bound to X.sup.2 and Z.sup.2; Z.sup.2 is is
independently selected from the groups discussed above.
In some embodiments, X.sup.1 and X.sup.2 may be the same. In other
cases, X.sup.1 and X.sup.2 may be different.
Disiloxanes
Without wishing to be bound by any theory, the estimated half-life
for hydrolysis of the disiloxane depicted here:
##STR00018## is 15 days based at pH5 in 90% DMSO/10% water at room
temperature based upon NMR experiments. Based on the effect of
alkyl group size on silyl ether hydrolysis, the half-life of
hydrolysis of the corresponding diphenyltetraethyldisiloxane is
expected to be more than ten fold longer. Thus in certain aqueous
situations, the hydrolysis of the dimeric disiloxane to monomeric
silanol may be essentially irreversible on the timescale relevant
for the biological functions they are modulating.
In another embodiment, the stability of a disiloxane linkage to
attack on silicon may be influenced by steric hindrance. Alkyl
groups on silicon of increasing size (e.g. Me<Et<iPr<tBu)
can promote disiloxane stability once formed, while at the same
time reducing the probability and rate of dimerization of the
silanol when two monomers are not held in close proximity.
An alternative approach to increasing steric hindrance about
silicon is depicted here:
##STR00019## Increasing steric hindrance about silicon may relate
to homo- or hetero-dimeric designs where Y and X are the connector
and ligand/pharmacophore moieties, respectively. Alternatively,
--Y--X could be connected through the respective R-groups.
Importantly, the nature of these groups can also influence the
stability of the disiloxy dimer and the rate of dimerization to
allow one to tune the properties.
In some instances, the incorporation of the silicon in a ring
system allows for steric hindrance by flanking substituents rather
than directly upon Si. Examples of two disiloxanes are depicted
here:
##STR00020## In these examples, selectivity and complementarity can
be further increased in designs such as those below where the
individual R.sup.2 component in a heterodimeric pairing may be
electron-rich and electron-poor aromatic or heteroaromatic rings,
such that the result quadrupole interactions stabilize the
alignment and association of monomers, and promote the dimerization
of hindered silanols to the disiloxane (e.g. where R.sup.3
substituents are electron withdrawing, producing a group like
C.sub.6F.sub.5, while R.sup.4 may be electron donating or H for a
simple phenyl). In a similar manner, other donor-acceptor
interactions such as cation (e.g. aminium)/aromatic systems may be
employed to promote association, alignment and dimerization.
Connectors
In some embodiments, a monomer may comprise a connector that joins
the ligand moiety with the linker element. In some instances, such
connectors do not have significant binding or other affinity to an
intended target. However, in certain embodiments, a connector may
contribute to the affinity of a ligand moiety to a target.
In some embodiments, a connector element may be used to connect the
linker element to the ligand moiety. In some instances, the
connector element may be used to adjust spacing between the linker
element and the ligand moiety. In some cases, the connector element
may be used to adjust the orientation of the linker element and the
ligand moiety. In certain embodiments, the spacing and/or
orientation the linker element relative to the ligand moiety can
affect the binding affinity of the ligand moiety (e.g., a
pharmacophore) to a target. In some cases, connectors with
restricted degrees of freedom are preferred to reduce the entropic
losses incurred upon the binding of a multimer to its target
biomolecule. In some embodiments, connectors with restricted
degrees of freedom are preferred to promote cellular permeability
of the monomer.
In some embodiments, the connector element may be used for modular
assembly of monomers. For example, in some instances, a connector
element may comprise a functional group formed from reaction of a
first and second molecule. In some cases, a series of ligand
moieties may be provided, where each ligand moiety comprises a
common functional group that can participate in a reaction with a
compatible functional group on a linker element. In some
embodiments, the connector element may comprise a spacer having a
first functional group that forms a bond with a ligand moiety and a
second functional group that forms a bond with a linker
element.
Contemplated connectors may be any acceptable (e.g.
pharmaceutically and/or chemically acceptable) bivalent linker
that, for example, does not interfere with multimerization of the
disclosed monomers. For instance, such linkers may be substituted
or unsubstituted C.sub.1-C.sub.10 alkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, acyl, sulfone,
sulfonamide, phosphate, ester, carbonate, carbamate, or amide.
Contemplated connectors may include polymeric connectors, such a
polyethylene glycol or other pharmaceutically acceptable polymers.
For example, contemplated connectors may be a covalent bond or a
bivalent C.sub.1-10 saturated or unsaturated, straight or branched,
hydrocarbon chain, wherein one, two, or three or four methylene
units of bivalent C.sub.1-10 are optionally and independently
replaced by cyclopropylene, --NR--, --N(R)C(O)--, --C(O)N(R)--,
--N(R)SO.sub.2--, --SO.sub.2N(R)--, --O--, --C(O)--, --OC(O)--,
--C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR)--, phenyl, or a mono or bicyclic heterocycle ring. In
some embodiments, a connector may be from about 7 atoms to about 13
atoms in length, or about 8 atoms to about 12 atoms, or about 9
atoms to about 11 atoms in length. For purposes of counting
connector length when a ring is present in the connector group, the
ring is counted as three atoms from one end to the other. In
another embodiment, a connecter group is from about 6 .ANG. to
about 15 .ANG. in length.
Methods
In some embodiments, a method of administering a pharmaceutically
effective amount of a multimeric compound to a patient in need
thereof is provided. In some cases, the method comprises
administering to the patient thereof an amount of the first monomer
and an amount of the second monomer in amounts effective such that
the pharmaceutically effective amount of the resulting multimer is
formed in vivo. For example, the multimer may be a dimer.
Alternatively, the multimer may be a trimer.
In some embodiments, a first monomer and a second monomer may be
administered substantially sequentially. In other embodiments, the
first monomer and the second monomer are administered substantially
simultaneously. In some embodiments the monomers may be
administered, sequentially or simultaneously, by different routes
of administration. In still further embodiments, a first monomer
and a second monomer may be administered after forming a
multimer.
In some instances, a method of modulating two or more target
biomolecule domains substantially simultaneously is provided. The
method comprises contacting an aqueous composition comprising said
biomolecular target domain with a first monomer represented by:
X.sup.1--Y.sup.1--Z.sup.1 (Formula I), and pharmaceutically
acceptable salts, stereoisomers, metabolites and hydrates thereof,
wherein X.sup.1 is a first ligand moiety capable of binding to and
modulating a first target biomolecule domain; and a second monomer
represented by: X.sup.2--Y.sup.2--Z.sup.2 (Formula II), and
pharmaceutically acceptable salts, stereoisomers, metabolites and
hydrates thereof, wherein X.sup.2 is a ligand moiety capable of
binding to and modulating a second target biomolecule domain;
wherein upon contact with the aqueous composition, said first
monomer and said second monomer forms a multimer that binds to the
first target biomolecule domain and the second target biomolecule
domain.
In certain embodiments, a method of treating a disease associated
with two or more target biomolecules in a patient in need thereof
is provided. The method comprises administering to said patient a
first monomer represented by: X.sup.1--Y.sup.1--Z.sup.1 (Formula
I), and pharmaceutically acceptable salts, stereoisomers,
metabolites and hydrates thereof, wherein X.sup.1 is a first ligand
moiety capable of binding to and modulating a first target
biomolecule domain; and administering to said patient a second
monomer represented by: X.sup.2--Y.sup.2--Z.sup.2 (Formula II),
wherein X.sup.2 is a second ligand moiety capable of binding to and
modulating a second target biomolecule domain, wherein upon
administration, said first monomer and said second monomer forms a
multimer in vivo that binds to the first target biomolecule domain
and the second target biomolecule domain.
In some embodiments, the target biomolecule may be a protein.
Alternatively, the target biomolecule may be a protein domain. In
other embodiments, the target biomolecule may be nucleic acid. In
some cases, the ligand moiety (e.g., ligand moiety) may be a
pharmacophore.
In some embodiments, a multimer may be used to inhibit or
facilitate protein-protein interactions. For example, in some
cases, a multimer may be capable of activating or inactivating a
signaling pathway. Without wishing to be bound by any theory, a
multimer may bind to a target protein and affect the conformation
of the target protein such that the target protein is more
biologically active as compared to when the multimer does not bind
the target protein. In some embodiments monomers may be chosen such
that a multimer formed from the monomers binds to at least two
regions of a target molecule.
In certain embodiments, the compounds may be selected from the
group consisting of:
(4-(3-(aminomethyl)phenyl)piperidin-1-yl)(4-((hydroxydimethylsilyl)methox-
y)-phenyl)methanone;
N-(4-(4-(3-(aminomethyl)phenyl)-piperidine-1-carbonyl)-2-chlorophenyl)-2--
(hydroxydimethylsilyl)acetamide;
N-(3-(4-(3-(aminomethyl)phenyl)piperidine-1-carbonyl)-phenyl)-2-(hydroxyd-
imethylsilyl)acetamide;
(4-(3-(aminomethyl)phenyl)piperidin-1-yl)(3-chloro-4-((hydroxydimethylsil-
yl)methoxy)-phenyl)methanone;
(4-(3-(aminomethyl)phenyl)-piperidin-1-yl)(3-((hydroxydimethylsilyl)-meth-
oxy)phenyl)methanone;
(4-(3-(aminomethyl)-phenyl)piperidin-1-yl)(3-chloro-5-((hydroxydimethylsi-
lyl)methoxy)phenyl)methanone;
N-(4-(4-(3-(aminomethyl)phenyl)-piperidine-1-carbonyl)phenyl)-2-(hydroxyd-
imethylsilyl)acetamide; and pharmaceutically acceptable salts,
stereoisomers, metabolites and hydrates thereof.
Without wishing to be bound by any theory, protein-protein and
protein-nucleic acid recognition often work through protein
interaction domains, such as the SH2, SH3, and PDZ domains.
Currently, there are over 75 such motifs reported in the literature
(Hunter, et al., Cell 100:113-127 (2000); Pawson et al., Genes
& Development 14:1027-1047 (2000)). For example, SH2 domains
are miniature receptors for protein regions containing a
phosphorylated tyrosine. SH2 domains may be found in proteins that
act as, or play a role in, for example, adaptors, scaffolds,
kinases, phosphatases, ras signalling, transcription,
ubiquitination, cytoskeletal regulation, signal regulation, and
phospholipid second messenger signaling. As another non-limiting
example, SH3 domains bind peptide loops with the motif RXXK or
PXXP. Many proteins have both SH2 and SH3 domains, which act as
"receptors" to bind one or more protein partners. Coferons may be
designed to inhibit binding of a phosphotyrosine protein to its
cognate SH2 domain. Alternatively, monomers and multimers may be
designed so one ligand binds one motif (i.e. SH2), and a second
ligand moiety binds a second motif (i.e. SH3), either on the same
or different proteins.
Many large proteins or macromolecular complexes (e.g., ribosomes)
have multiple binding sites with known drug inhibitors. In some
embodiments, linker elements may be used to bring together two
pharmacophores on the same target to: (i) bind the target with
higher affinity; (ii) exhibit a stronger inhibition than either
pharmacophore alone; (iii) exhibit greater activation than either
pharmacophore alone; or (iv) create a binding entity covering a
larger surface area of the target, making it harder for the
organism/cell/virus to develop resistance to the drug via point
mutations.
In some embodiments, a multimer may target a tryptase. For example,
a multimer may be used to treat conditions activated by a trypase,
such as mast cell mediated inflammatory conditions (e.g. asthma).
Asthma is frequently characterized by progressive development of
hyper-responsiveness of the trachea and bronchi to both
immunospecific allergens and generalized chemical or physical
stimuli, which lead to the onset of chronic inflammation.
Leukocytes containing IgE receptors, notably mast cells and
basophils, are present in the epithelium and underlying smooth
muscle tissues of bronchi. These leukocytes initially become
activated by the binding of specific inhaled antigens to the IgE
receptors and then release a number of chemical mediators. For
example, degranulation of mast cells leads to the release of
proteoglycans, peroxidase, arylsulfatase B, chymase, and tryptase,
which results in bronchiole constriction.
Human mast cell .beta.-tryptase-II is a tetrameric serine protease
that is concentrated in mast cell secretory granules. The enzyme is
involved in IgE-induced mast cell degranulation in an allergic
response and is potentially a target for the treatment of allergic
asthma, rhinitis, conjunctivitis and dermatitis. Tryptase has also
been implicated in the progression of renal, pulmonary, hepatic,
testicular fibrosis, chronic obstructive pulmonary disease (COPD)
and inflammatory conditions such as ulcerative colitis,
inflammatory bowel disease, rheumatoid arthritis, and various other
mast cell-related diseases. In some embodiments, multimers may be
used to treat such diseases.
Tryptase is stored in the mast cell secretory granules and is the
major protease of human mast cells. Tryptase has been implicated in
a variety of biological processes, including degradation of
vasodilatory and bronchodilatory neuropeptides and modulation of
bronchial responsiveness to histamine. As a result, tryptase
inhibitors may be useful as anti-inflammatory agents for treatment
of inflammatory disease and may also be useful in treating or
preventing allergic rhinitis, inflammatory bowel disease,
psoriasis, ocular or vernal or ulcerative conjunctivitis,
dermatological conditions (e.g., psoriasis, eczema, or atopic
dermatitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis,
hematoid arthritis, traumatic arthritis, rubella arthritis,
psoriatic arthritis, or gouty arthritis), rheumatoid spondylitis,
interstitial lung disease, chronic obstructive pulmonary disease,
and diseases of joint cartilage destruction.
In addition, tryptase has been shown to be a potent mitogen for
fibroblasts, suggesting its involvement in the pulmonary fibrosis
in asthma and interstitial lung diseases. Therefore, in some
embodiments, tryptase inhibitors may be useful in treating or
preventing fibrotic conditions, for example, fibrosis,
sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial
fibrosis, neurofibromas, hepatic fibrosis, renal fibrosis,
testicular, and hypertrophic scars.
Additionally, tryptase inhibitors may be useful in treating or
preventing myocardial infarction, stroke, angina and other
consequences of atherosclerotic plaque rupture.
Tryptase has also been discovered to activate prostromelysin that
in turn activates collagenase, thereby initiating the destruction
of cartilage and periodontal connective tissue, respectively. In
some embodiments, tryptase inhibitors may be useful in the
treatment or prevention of arthritis, periodontal disease, diabetic
retinopathy, a condition relating to atherosclerotic plaque
rupture, anaphylatis ulcerative colitis, and tumour growth. Also,
tryptase inhibitors may be useful in the treatment of anaphylaxis,
multiple sclerosis, peptic ulcers, and syncytial viral
infections.
A variety of antibiotics elicit their antibacterial activity by
binding to the bacterial ribosome and inhibiting protein synthesis.
Many of these antibiotics bind the peptidyl transferase center of
the ribosome (P site). In some embodiments, a multimer may bind to
two or more sites on the ribosome. For example, a first
pharmacophore of a multimer may bind to the peptidyl transferase
center of the ribosome (i.e., the P site) and a second multimer may
bind to site adjacent to the P site. As a non-limiting,
illustrative example, Linezolid, an oxazolidinone antibiotic, is
believed to bind adjacent to the binding site for Sparsomycin. The
close juxtaposition of the linezolid binding site with the
sparosmycin binding site presents a possible scenario for
developing monomers based on linezolid and sparsomycin that can
dimerize on binding to the ribosome, thereby creating a high
affinity and high specificity inhibitor of bacterial protein
synthesis.
Other non-limiting examples of target protein families are provided
in Table 1 below. Also provided in Table 1 are endogenous ligands,
agonists, and antagonists that bind to the protein families.
Examples of detection assays are also provided in Table 1, which
may be used in a screening assay to detect activation and/or
inhibition of the target protein.
Provided in Table 2 are non-limiting examples of domains that can
bind a ligand, proteins that contain the domains, known inhibitors,
and K.sub.D values of binding partners (i.e., ligands). Examples of
detection assays are also provided in Table 2, which may be used in
a screening assay to find ligands for the domains.
TABLE-US-00001 TABLE 1 Examples of Protein Families and Their
Pharmacological Targets EXAMPLES OF EXAMPLES OF ENDOGENOUS CURRENT
CURRENT EXAMPLES OF TARGET TARGET LIGAND AGONISTS ANTAGONISTS
DETECTION FAMILY EXAMPLE (MODULATORS) (ACTIVATORS) (INHIBITORS)
ASSAYS G-PROTEIN .beta..sub.2 adrenergic epinephrine, albuterol,
propranolol, HitHunter, PathHunter COUPLED receptors norepinephrine
salbutamol, butoxamine (DiscoverX), cAMP RECEPTORS terbutaline,
assay, Intracellular salmeterol calcium flux, TANGO, GeneBlazer,
ELISA, binding assays G-PROTEIN Muscarinic Acetylcholine
Acetylcholine, Scopolamine, HitHunter, PathHunter COUPLED receptors
Pilocarpine atropine, (DiscoverX), cAMP RECEPTORS ipratropium,
assay, Intracellular caproctamine calcium flux, TANGO, GeneBlazer,
ELISA, binding assays G-PROTEIN H1 histamine histamine Histamine
diphenhydramine, HitHunter, PathHunter COUPLED receptor doxylamine,
(DiscoverX), cAMP RECEPTORS pyrilamine, assay, Intracellular
brompheniramine, calcium flux, TANGO, chlorpheniramine, GeneBlazer,
ELISA, Loratadine, binding assays Fexofenadine, Cetirizine,
Desloratadine NUCLEAR Estrogen Estriol, estrone, 17-beta-estradiol,
Tamoxifen, ICI Hit-hunter RECEPTORS receptor estradiol
Chlorotrianisene, 164,384, (Discoverx), reporter Dienestrol,
Keoxifene, assays, TANGO, Fosfestrol, Mepitiostane GeneBlazer,
ELISA, Diethylstilbestrol, ligand binding assays, Zeranol VOLTAGE
voltage-gated veratridine, tetrodotoxin, Intracellular ion flux
GATED ION sodium aconitine saxitoxin, assays CHANNELS channels
VOLTAGE voltage-gated BAY K 8644, .omega.-conotoxin, .omega.-
Intracellular ion flux GATED ION calcium CGP 28392 agatoxins,
assays CHANNELS channels dihydropyridine, nifedipine LIGAND kainate
glutamate kainic acid, CNQX, HitHunter, PathHunter GATED ION
receptor domoic acid, LY293558, (DiscoverX), cAMP CHANNELS
LY339434, LY294486 assay, Intracellular ion ATPA, flux, TANGO,
iodowillardiine, GeneBlazer, ELISA, (2S,4R)-4- ligand binding
assays, methylglutamic acid RECEPTOR epidermal epidermal growth
EGF, TGFa, PD153035, anti- reporter assays, kinase TYROSINE growth
factor factor amphiregulin, EGFR antibody assays, CO-IP, BRET,
KINASES receptor betacellulin, C225, FRET, TANGO, (EGFR)
epiregulin, aeroplysinin-1, GeneBlazer, neuregulins AG18, AG82,
HitHunter, PathHunter AG99, AG112, (DiscoverX), ELISA AG213, AG490,
AG494, AG527, AG555, AG556 GROWTH Vascular VEGFR Ranibizumab,
Hit-hunter FACTORS endothelial bevacizumab, (Discoverx), reporter
growth factor sunitinib, assays, TANGO, sorafenib, GeneBlazer,
ELISA, axitinib, ligand binding assays, pazopanib, Naphthamides
PROTEASES Caspase granzyme B; Granzyme B, Z-VAD(OMe)- caspase
assays, caspase caspase FMK, Z-VAD- apoptosis assays, CHO
mitochondrial Dy, CO- IP, BRET, FRET, TANGO, GeneBlazer, HitHunter,
PathHunter (DiscoverX), ELISA PHOSPHATASES PP1
phosphoserine/threonine calyculin A, protein tyrosine residues
nodularin, phosphatase assay, tautomycin CO-IP, BRET, FRET, TANGO,
GeneBlazer, HitHunter, PathHunter (DiscoverX), ELISA PROTEIN ERR
MEK AG126, kinase assay, CO-IP, KINASES apigenin, Ste- BRET, FRET,
MPKKKPTPTQL reporter assays, NP-NH2 TANGO, GeneBlazer, (SEQ ID NO:
1) HitHunter, PathHunter H-GYGRKKRRQR (DiscoverX) RR-G- MPKKKPTPIQL
NP-NH2 (SEQ ID NO: 2) PD98059, U0126, MISC Adenylate G proteins,
bordetella NKY80, 2',3'- BRET, FRET, calcium ENZYMES cyclase
calcium pertussis, Dideoxyadenosine, flux assays, cAMP cholera
toxin, 2',5'- assays, TANGO, forskolin Dideoxyadenosine,
GeneBlazer, SQ22536, HitHunter, PathHunter MDL-12330A (DiscoverX)
MISC Acetylcholine Caproctamine, Acetylcholinesterase ENZYMES
sterase Metrifonate, Assay, Amplex Red, Physostigmine, Ellman
method, HPLC Galantamine, Dyflos, Neostigmine BIOACTIVE Ceramide
sphingomyelin TNF Fas fumonisin B TLC lipid charring, LIPIDS
ligand, 1,25 diacylglycerol kinase dihydroxy labeling in vitro
vitamin D, interferon CYTOKINES IL2 IL2R BAY 50-4798, daclizumab,
TANGO, GeneBlazer, P1-30, SP4206 basiliximab, HitHunter, PathHunter
SP4206 (DiscoverX), IL2 dependent mouse CTLL cell line, ELISA MISC
BCLXL BAD BH3I-1, A- TANGO, GeneBlazer, PROTEINS 371191, ABT-
HitHunter, PathHunter 737 (DiscoverX), CO-IP, BRET, FRET, ELISA
MISC p53 MDM2, JNK1-3, PRIMA-1, Pifithrin-.alpha. caspase assays,
PROTEINS ERK1-2, p38 MIRA-1, RITA, apoptosis assays, MAPK, ATR,
mitochondrial Dy, CO- ATM, Chk1, IP, BRET, FRET, Chk2, DNA-PK,
TANGO, GeneBlazer, CAK HitHunter, PathHunter (DiscoverX), ELISA
MISC Tubulin tubulin ALB109564, kinase assay, CO-IP, PROTEINS
ABT-751, BRET, FRET, D24851, reporter assays, D64131, TANGO,
GeneBlazer, benomyl, .delta.-arrestin(DiscoverX estramustine,
LY290181 MISC .quadrature.-amyloid L 1,10- Stagnant Amyloid
PROTEINS phenanthroline Fibril Formation derivatives, Assay,
amyloid KLVFF fibrillization assay (SEQ ID NO: 3), LVFFA (SEQ ID
NO: 4), Memoquin, SLF- CR MISC thymidylate raltitrexed, caspase
assays, PROTEINS synthase pemetrexed, apoptosis assays, nolatrexed,
mitochondrial Dy, CO- ZD9331, IP, BRET, FRET, GS7904L, TANGO,
GeneBlazer, fluorouracil HitHunter, PathHunter (DiscoverX), ELISA
UBIQUITIN MDM2 p53 trans-4-Iodo, 4'- TANGO, GeneBlazer, LIGASES
boranyl- HitHunter, PathHunter chalcone, (DiscoverX), CO-IP,
Nutlins, MI-219, BRET, FRET, ELISA, MI-63, RITA, reporter assay
HLI98 VIRAL HPV E2 HPV E1 indandiones, E2 displacement assay,
REGULATORS podophyllotoxin TANGO, GeneBlazer, HitHunter, PathHunter
(DiscoverX), CO-IP, BRET, FRET, ELISA, reporter assay BACTERIAL
ZipA FtsZ substituted 3-(2- TANGO, GeneBlazer, CELL
indolyl)piperidines, HitHunter, PathHunter DIVISION 2-phenyl
DiscoverX), CO-IP, PROTEINS indoles BRET, FRET, ELISA, reporter
assay, polarization competition assay, CYTOKINES TNF TNFR
infliximab, TANGO, GeneBlazer, adalimumab, HitHunter, PathHunter
etanercept (DiscoverX), CO-IP, BRET, FRET, ELISA, SCAFFOLD JIP1 JNK
BI-78D3, TIJIP TANGO, GeneBlazer, PROTEINS HitHunter, PathHunter
(DiscoverX), CO-IP, BRET, FRET, ELISA, kinase assay DNA REPAIR PARP
INO-1001, TANGO, GeneBlazer, AG014699, BS- HitHunter, PathHunter
201, AZD2281, (DiscoverX), CO-IP, BS-401 BRET, FRET, ELISA,
RIBOSOMES Antibiotics ribosomes tetracyclins, cell death assay,
macrolides, lincosamides, streptogramins HISTONE HDAC1
suberoylanilide TANGO, GeneBlazer, DEACETYLASES hydroxamic acid,
HitHunter, PathHunter trichostatin A, (DiscoverX), CO-IP, LBH589
BRET, FRET, ELISA, APOPTOSIS XIAP SMAC/DIABLO, SM102-SM130 CO-IP,
BRET, FRET, REGULATORS caspase 3, caspase reporter assays, 7,
caspase 9 TANGO, GeneBlazer, HitHunter, PathHunter (DiscoverX),
cell death assays CHAPERONE Hsp90 Cdc37, survivin Celastrol, CO-IP,
BRET, FRET, PROTEINS shepherdin reporter assays, TANGO, GeneBlazer,
HitHunter, PathHunter (DiscoverX), SERINE/THREONINE mTOR Raptor,
Rapamycin, kinase assay, CO-IP, PROTEIN mLST8/G.beta.L caffeine,
BRET, FRET, KINASES farnesylthiosalicylic reporter assays, acid,
TANGO, GeneBlazer, curcumin, HitHunter, PathHunter temsirolimus,
(DiscoverX) everolimus SERINE/THREONINE- B-raf & B-raf K-ras
PLX4720 kinase assay, CO-IP, PROTEIN V600E BRET, FRET, KINASES
reporter assays, TANGO, GeneBlazer, HitHunter, PathHunter
(DiscoverX), CYCLIN CDK2 Cyclin A, cyclin E Variolin, kinase assay,
CO-IP, DEPENDENT Meriolin BRET, FRET, KINASES reporter assays,
TANGO, GeneBlazer, HitHunter, PathHunter (DiscoverX), GROWTH IGF-1R
IGFII PQIP CO-IP, BRET, FRET, FACTOR reporter assays, RECEPTORS
TANGO, GeneBlazer, HitHunter, PathHunter (DiscoverX), PROTEASOME
20S 19S Bortezomib, CO-IP, BRET, FRET, salinosporamide cell
viability A,
TABLE-US-00002 TABLE 2 Examples of Protein Domains EXAMPLE OF
EXAMPLES APPROXIMATE PROTEIN EXAMPLES OF OF K.sub.D OF CONTAINING
KNOWN DETECTION BINDING DOMAIN PARTNER DOMAIN INHIBITORS ASSAYS
PARTNERS SH2 Phospho-tyrosine Grb2 Fmoc-Glu-Tyr-Aib- Surface 0.2-11
.mu.M residues Asn-NH2 plasmon (SEQ ID NO: 5): resonance
Ac-SpYVNVQ-NH2 (SPR) (SEQ ID NO: 6), technology, macrocycles,
STATTIC FHA Phospho-threonine KIF13B 1-100 .mu.M and phospho-
tyrosine residues 14-3-3 Phospho-serine 14-3-3 R18 7 nM-20 .mu.M
residues WW ligands containing Pin1 Zn(II) 6 .mu.M-190 .mu.M PpxY,
Proline-rich Dipicolylamine- sequences based artificial receptors
WD40 Apaf-1 1 .mu.M MH2 phospho-serine SMAD2 240 nM residues BROMO
acetylated lysine CBP 1 .mu.M-4 mM residues UBA mono-, di-, tri-,
and IIIIR23A 6 .mu.M-2.35 mM tetra-ubiquitin PTB Phospho-tyrosine
IRS-1 LSNPTX-NH2 PTB domain 160 nM-10 .mu.M (SEQ ID NO: 7), binding
residues, Asn-Pro-X- LYASSNPAX-NH2 assays Tyr motifs (SEQ ID NO: 8)
SH3 Proline-rich peptides Grb2 Peptidimer-c, 1-500 .mu.M with
consensus Pro- VPPPVPPRRR X-X-Pro, (SEQ ID NO: 9), (VPPPVPPRRR)
(SEQ ID NO: 9))2K) EVH1 FPx.PHI.P motifs, ActA 10-50 .mu.M PPxxF
motifs GYF proline-rich CDBP2 10-160 .mu.M sequences, VHS TOM1
11-50 .mu.M PDZ PDZ, Val-COOH MNT1 NSC668036, FJ9 1-500 .mu.M PUF
RNA PUM1 10-100 nM TUBBY DNA, TULP1 phosphotidylinositol SAM CNK 71
nM-1 .mu.M DD DD FADD CARD CARD Apaf-1 1.4 .mu.M PyD PyD Pyrin 4
.mu.M PB1 PB1 Bem1 4-500 nM BRCT BRCT BRCA1 113 nM-6 .mu.M PH
phosphatidylinositol- AKT1 NSC 348900, 1.76 nM-350 .mu.M
4,5-bisphosphate, perifosine, SH5, PI-3, 4-P2 or PI- SH23, SH24,
SH25, 3,4,5-P3 ml14, ml15, ml16 FYVE Phosphatidylinositol SARA 50
nM-140 .mu.M 3-phosphate, zinc C1 phorbol esters, PKC isoforms
0.58-800 nM diacylglycerol FERM PI(3)P, PI(4)P, PTLP1 200 nM-30
.mu.M PI(5)P, IP3, C2 Calcium, acidic Nedd4 250 nM-94 .mu.M
phospholipids PX PI(3,4)P2, PI(3)P, CISK 1.8 nM-50 .mu.M PI(3,5)P2,
PI(4)P, PI(5)P, PI(3,4,5)P3, PI(4,5)P2 ENTH PtdIns(4,5)P2, Epsin1
98 nM-1 .mu.M PtdIns(1,4,5)P3, PI(3,4)P2; PI(3,5)P2
A pharmacophore is typically an arrangement of the substituents of
a moiety that confers biochemical or pharmacological effects. In
some embodiments, identification of a pharmacophore may be
facilitated by knowing the structure of the ligand in association
with a target biomolecule. In some cases, pharmacophores may be
moieties derived from molecules previously known to bind to target
biomolecules (e.g., proteins), fragments identified, for example,
through NMR or crystallographic screening efforts, molecules that
have been discovered to bind to target proteins after performing
high-throughput screening of natural products libraries, previously
synthesized commercial or non-commercial combinatorial compound
libraries, or molecules that are discovered to bind to target
proteins by screening of newly synthesized combinatorial libraries.
Since most pre-existing combinatorial libraries are limited in the
structural space and diversity that they encompass, newly
synthesized combinatorial libraries may include molecules that are
based on a variety of scaffolds.
Additionally pharmacophores may be derived from traditional
approaches such as fragment based drug design and structure based
drug design. Those skilled in the art will recognize that any
pharmacophore including pre-existing pharmacophores such as
approved drugs are amenable to be designed as monomers through the
incorporation of the appropriate linker elements and connector
elements. For example, previously approved drugs that have poor
efficacy due to a low affinity for a first macromolecular target
may be utilized as a pharmacophore component of a first monomer
which when combined with a pharmacophore of a second monomer that
also binds the first macromolecular target or a second
macromolecular target that interacts with the first macromolecular
target results in enhanced binding and, in some cases, higher
efficacy. Likewise, previously approved drugs that have low
efficacy as a result of size, molecular weight or other
physicochemical attributes that reduce the cellular uptake of the
drug may be amenable to being converted into one or more monomers
that bear the appropriate pharmacophoric elements, such that each
monomer has physicochemical attributes that allow for increased
cellular uptake.
In some embodiments, a ligand moiety (e.g., a pharmacophore) may
have a molecular weight between 50 Da and 2000 Da, in some
embodiments between 50 Da and 1500 Da, in some embodiments, between
50 Da and 1000 Da, and in some embodiments, between 50 Da and 500
Da. In certain embodiments, a ligand moiety may have a molecular
weight of less than 2000 Da, in some embodiments, less than 1000
Da, and in some embodiments less than 500 Da.
In certain embodiments, the compound utilized by one or more of the
foregoing methods is one of the generic, subgeneric, or specific
compounds described herein.
Disclosed compositions may be administered to patients (animals and
humans) in need of such treatment in dosages that will provide
optimal pharmaceutical efficacy. It will be appreciated that the
dose required for use in any particular application will vary from
patient to patient, not only with the particular compound or
composition selected, but also with the route of administration,
the nature of the condition being treated, the age and condition of
the patient, concurrent medication or special diets then being
followed by the patient, and other factors which those skilled in
the art will recognize, with the appropriate dosage ultimately
being at the discretion of the attendant physician. For treating
clinical conditions and diseases noted above, a compound may be
administered orally, subcutaneously, topically, parenterally, by
inhalation spray or rectally in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants, and vehicles. Parenteral administration may include
subcutaneous injections, intravenous or intramuscular injections,
or infusion techniques.
Treatment can be continued for as long or as short a period as
desired. The compositions may be administered on a regimen of, for
example, one to four or more times per day. A suitable treatment
period can be, for example, at least about one week, at least about
two weeks, at least about one month, at least about six months, at
least about 1 year, or indefinitely. A treatment period can
terminate when a desired result, for example a partial or total
alleviation of symptoms, is achieved.
In another aspect, pharmaceutical compositions comprising monomers,
dimers, and/or multimers as disclosed herein formulated together
with a pharmaceutically acceptable carrier provided. In particular,
the present disclosure provides pharmaceutical compositions
comprising monomers, dimers, and/or multimers as disclosed herein
formulated together with one or more pharmaceutically acceptable
carriers. These formulations include those suitable for oral,
rectal, topical, buccal, parenteral (e.g., subcutaneous,
intramuscular, intradermal, or intravenous) rectal, vaginal, or
aerosol administration, although the most suitable form of
administration in any given case will depend on the degree and
severity of the condition being treated and on the nature of the
particular compound being used. For example, disclosed compositions
may be formulated as a unit dose, and/or may be formulated for oral
or subcutaneous administration.
Exemplary pharmaceutical compositions may be used in the form of a
pharmaceutical preparation, for example, in solid, semisolid, or
liquid form, which contains one or more of the compounds, as an
active ingredient, in admixture with an organic or inorganic
carrier or excipient suitable for external, enteral, or parenteral
applications. The active ingredient may be compounded, for example,
with the usual non-toxic, pharmaceutically acceptable carriers for
tablets, pellets, capsules, suppositories, solutions, emulsions,
suspensions, and any other form suitable for use. The active object
compound is included in the pharmaceutical composition in an amount
sufficient to produce the desired effect upon the process or
condition of the disease.
For preparing solid compositions such as tablets, the principal
active ingredient may be mixed with a pharmaceutical carrier, e.g.,
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g., water, to form a solid preformulation composition containing
a homogeneous mixture of a compound, or a non-toxic
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective unit dosage forms such as tablets, pills and
capsules.
In solid dosage forms for oral administration (capsules, tablets,
pills, dragees, powders, granules and the like), the subject
composition is mixed with one or more pharmaceutically acceptable
carriers, such as sodium citrate or dicalcium phosphate, and/or any
of the following: (1) fillers or extenders, such as starches,
lactose, sucrose, glucose, mannitol, and/or silicic acid; (2)
binders, such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)
humectants, such as glycerol; (4) disintegrating agents, such as
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate; (5) solution
retarding agents, such as paraffin; (6) absorption accelerators,
such as quaternary ammonium compounds; (7) wetting agents, such as,
for example, acetyl alcohol and glycerol monostearate; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
a talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof; and (10)
coloring agents. In the case of capsules, tablets and pills, the
compositions may also comprise buffering agents. Solid compositions
of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or
milk sugars, as well as high molecular weight polyethylene glycols
and the like.
A tablet may be made by compression or molding, optionally with one
or more accessory ingredients. Compressed tablets may be prepared
using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the subject composition moistened with an inert liquid
diluent. Tablets, and other solid dosage forms, such as dragees,
capsules, pills and granules, may optionally be scored or prepared
with coatings and shells, such as enteric coatings and other
coatings well known in the pharmaceutical-formulating art.
Compositions for inhalation or insufflation include solutions and
suspensions in pharmaceutically acceptable, aqueous or organic
solvents, or mixtures thereof, and powders. Liquid dosage forms for
oral administration include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the subject composition, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, cyclodextrins and mixtures thereof.
Suspensions, in addition to the subject composition, may contain
suspending agents as, for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, and mixtures thereof.
Formulations for rectal or vaginal administration may be presented
as a suppository, which may be prepared by mixing a subject
composition with one or more suitable non-irritating excipients or
carriers comprising, for example, cocoa butter, polyethylene
glycol, a suppository wax or a salicylate, and which is solid at
room temperature, but liquid at body temperature and, therefore,
will melt in the body cavity and release the active agent.
Dosage forms for transdermal administration of a subject
composition includes powders, sprays, ointments, pastes, creams,
lotions, gels, solutions, patches and inhalants. The active
component may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to
a subject composition, excipients, such as animal and vegetable
fats, oils, waxes, paraffins, starch, tragacanth, cellulose
derivatives, polyethylene glycols, silicones, bentonites, silicic
acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays may contain, in addition to a subject
composition, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays may additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
Compositions and compounds may alternatively be administered by
aerosol. This is accomplished by preparing an aqueous aerosol,
liposomal preparation or solid particles containing the compound. A
non-aqueous (e.g., fluorocarbon propellant) suspension could be
used. Sonic nebulizers may be used because they minimize exposing
the agent to shear, which may result in degradation of the
compounds contained in the subject compositions. Ordinarily, an
aqueous aerosol is made by formulating an aqueous solution or
suspension of a subject composition together with conventional
pharmaceutically acceptable carriers and stabilizers. The carriers
and stabilizers vary with the requirements of the particular
subject composition, but typically include non-ionic surfactants
(Tweens, Pluronics, or polyethylene glycol), innocuous proteins
like serum albumin, sorbitan esters, oleic acid, lecithin, amino
acids such as glycine, buffers, salts, sugars, or sugar alcohols.
Aerosols generally are prepared from isotonic solutions.
Pharmaceutical compositions suitable for parenteral administration
comprise a subject composition in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
antioxidants, buffers, bacteriostats, solutes which render the
formulation isotonic with the blood of the intended recipient or
suspending or thickening agents.
Examples of suitable aqueous and non-aqueous carriers which may be
employed in the pharmaceutical compositions include water, ethanol,
polyols (such as glycerol, propylene glycol, polyethylene glycol,
and the like), and suitable mixtures thereof, vegetable oils, such
as olive oil, and injectable organic esters, such as ethyl oleate
and cyclodextrins. Proper fluidity may be maintained, for example,
by the use of coating materials, such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants
In another aspect, enteral pharmaceutical formulations including a
disclosed pharmaceutical composition comprising monomers, dimers,
and/or multimers, an enteric material; and a pharmaceutically
acceptable carrier or excipient thereof are provided. Enteric
materials refer to polymers that are substantially insoluble in the
acidic environment of the stomach, and that are predominantly
soluble in intestinal fluids at specific pHs. The small intestine
is the part of the gastrointestinal tract (gut) between the stomach
and the large intestine, and includes the duodenum, jejunum, and
ileum. The pH of the duodenum is about 5.5, the pH of the jejunum
is about 6.5 and the pH of the distal ileum is about 7.5.
Accordingly, enteric materials are not soluble, for example, until
a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of
about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6,
of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about
7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of
about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4,
of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric
materials include cellulose acetate phthalate (CAP), hydroxypropyl
methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate
(PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS),
cellulose acetate trimellitate, hydroxypropyl methylcellulose
succinate, cellulose acetate succinate, cellulose acetate
hexahydrophthalate, cellulose propionate phthalate, cellulose
acetate maleat, cellulose acetate butyrate, cellulose acetate
propionate, copolymer of methylmethacrylic acid and methyl
methacrylate, copolymer of methyl acrylate, methylmethacrylate and
methacrylic acid, copolymer of methylvinyl ether and maleic
anhydride (Gantrez ES series), ethyl
methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl
acrylate copolymer, natural resins such as zein, shellac and copal
collophorium, and several commercially available enteric dispersion
systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100,
Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and
Aquateric). The solubility of each of the above materials is either
known or is readily determinable in vitro. The foregoing is a list
of possible materials, but one of skill in the art with the benefit
of the disclosure would recognize that it is not comprehensive and
that there are other enteric materials that may be used.
Advantageously, kits are provided containing one or more
compositions each including the same or different monomers. Such
kits include a suitable dosage form such as those described above
and instructions describing the method of using such dosage form to
treat a disease or condition. The instructions would direct the
consumer or medical personnel to administer the dosage form
according to administration modes known to those skilled in the
art. Such kits could advantageously be packaged and sold in single
or multiple kit units. An example of such a kit is a so-called
blister pack. Blister packs are well known in the packaging
industry and are being widely used for the packaging of
pharmaceutical unit dosage forms (tablets, capsules, and the like).
Blister packs generally consist of a sheet of relatively stiff
material covered with a foil of a preferably transparent plastic
material. During the packaging process recesses are formed in the
plastic foil. The recesses have the size and shape of the tablets
or capsules to be packed. Next, the tablets or capsules are placed
in the recesses and the sheet of relatively stiff material is
sealed against the plastic foil at the face of the foil which is
opposite from the direction in which the recesses were formed. As a
result, the tablets or capsules are sealed in the recesses between
the plastic foil and the sheet. Preferably the strength of the
sheet is such that the tablets or capsules can be removed from the
blister pack by manually applying pressure on the recesses whereby
an opening is formed in the sheet at the place of the recess. The
tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in
the form of numbers next to the tablets or capsules whereby the
numbers correspond with the days of the regimen which the tablets
or capsules so specified should be ingested. Another example of
such a memory aid is a calendar printed on the card, e.g., as
follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week,
Monday, Tuesday, . . . " etc. Other variations of memory aids will
be readily apparent. A "daily dose" can be a single tablet or
capsule or several pills or capsules to be taken on a given day.
Also, a daily dose of a first compound can consist of one tablet or
capsule while a daily dose of the second compound can consist of
several tablets or capsules and vice versa. The memory aid should
reflect this.
Also contemplated herein are methods and compositions that include
additional active agents, or administering additional active
agents.
Also contemplated herein are methods and compositions that include
additional active agents, or administering additional active
agents.
Certain terms employed in the specification, examples, and appended
claims are collected here. These definitions should be read in
light of the entirety of the disclosure and understood as by a
person of skill in the art. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by a person of ordinary skill in the art.
Definitions
In some embodiments, the compounds, as described herein, may be
substituted with any number of substituents or functional moieties.
In general, the term "substituted" whether preceded by the term
"optionally" or not, and substituents contained in formulas, refer
to the replacement of hydrogen radicals in a given structure with
the radical of a specified substituent.
In some instances, when more than one position in any given
structure may be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at every position.
As used herein, the term "substituted" is contemplated to include
all permissible substituents of organic compounds. In a broad
aspect, the permissible substituents include acyclic and cyclic,
branched and unbranched, carbocyclic and heterocyclic, aromatic and
non-aromatic substituents of organic compounds. In some
embodiments, heteroatoms such as nitrogen may have hydrogen
substituents and/or any permissible substituents of organic
compounds described herein which satisfy the valencies of the
heteroatoms. Non-limiting examples of substituents include acyl;
aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl;
heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy;
heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy;
aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; oxo; --F; --Cl; --Br; --I; --OH;
--NO.sub.2; --CN; --SCN; --SR.sub.x; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --OR.sub.x, --C(O)R.sub.x;
--CO.sub.2(R.sub.x); --C(O)N(R.sub.x).sub.2; --OC(O)R.sub.x;
--OCO.sub.2R.sub.x; --OC(O)N(R.sub.x).sub.2; --N(R.sub.x).sub.2;
--SOR.sub.x; --S(O).sub.2R.sub.x; --NR.sub.xC(O)R.sub.x; or
--C(R.sub.x).sub.3; wherein each occurrence of R.sub.x
independently includes, but is not limited to, hydrogen, aliphatic,
heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl,
wherein any of the aliphatic, heteroaliphatic, arylalkyl, or
heteroarylalkyl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
Furthermore, the compounds described herein are not intended to be
limited in any manner by the permissible substituents of organic
compounds. In some embodiments, combinations of substituents and
variables described herein may be preferably those that result in
the formation of stable compounds. The term "stable," as used
herein, refers to compounds which possess stability sufficient to
allow manufacture and which maintain the integrity of the compound
for a sufficient period of time to be detected and preferably for a
sufficient period of time to be useful for the purposes detailed
herein.
The term "acyl," as used herein, refers to a moiety that includes a
carbonyl group. In some embodiments, an acyl group may have a
general formula selected from --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--C(O)N(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x; and
--OC(O)N(R.sub.x).sub.2; wherein each occurrence of R.sub.x
independently includes, but is not limited to, hydrogen, aliphatic,
heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl,
wherein any of the aliphatic, heteroaliphatic, arylalkyl, or
heteroarylalkyl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
The term "aliphatic," as used herein, includes both saturated and
unsaturated, straight chain (i.e., unbranched), branched, acyclic,
cyclic, or polycyclic aliphatic hydrocarbons, which are optionally
substituted with one or more functional groups. As will be
appreciated by one of ordinary skill in the art, "aliphatic" is
intended herein to include, but is not limited to, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. The
term "heteroaliphatic," as used herein, refers to aliphatic
moieties that contain one or more oxygen, sulfur, nitrogen,
phosphorus, or silicon atoms, e.g., in place of carbon atoms.
Heteroaliphatic moieties may be branched, unbranched, cyclic or
acyclic and include saturated and unsaturated heterocycles such as
morpholino, pyrrolidinyl, etc. In certain embodiments,
heteroaliphatic moieties are substituted by independent replacement
of one or more of the hydrogen atoms thereon with one or more
moieties including, but not limited to acyl; aliphatic;
heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl;
alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy;
heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; oxo; --F; --Cl; --Br; --I; --OH; --NO.sub.2; --CN;
--SCN; --SR.sub.x; --CF.sub.3; --CH.sub.2CF.sub.3; --CHCl.sub.1-2;
--CH.sub.2OH; --CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --OR.sub.x, --C(O)R.sub.x;
--CO.sub.2(R.sub.x); --C(O)N(R.sub.x).sub.2; --OC(O)R.sub.x;
--OCO.sub.2R.sub.x; --OC(O)N(R.sub.x).sub.2; --N(R.sub.x).sub.2;
--SOR.sub.x; --S(O).sub.2R.sub.x; --NR.sub.xC(O)R.sub.x; or
--C(R.sub.x).sub.3; wherein each occurrence of R.sub.x
independently includes, but is not limited to, hydrogen, aliphatic,
heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl,
wherein any of the aliphatic, heteroaliphatic, arylalkyl, or
heteroarylalkyl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
In general, the terms "aryl" and "heteroaryl," as used herein,
refer to stable mono- or polycyclic, heterocyclic, polycyclic, and
polyheterocyclic unsaturated moieties having preferably 3-14 carbon
atoms, each of which may be substituted or unsubstituted.
Substituents include, but are not limited to, any of the previously
mentioned substituents, i.e., the substituents recited for
aliphatic moieties, or for other moieties as disclosed herein,
resulting in the formation of a stable compound. In certain
embodiments, aryl refers to a mono- or bicyclic carbocyclic ring
system having one or two aromatic rings including, but not limited
to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the
like. In certain embodiments, the term heteroaryl, as used herein,
refers to a cyclic aromatic radical having from five to ten ring
atoms of which one ring atom is selected from the group consisting
of S, O, and N; zero, one, or two ring atoms are additional
heteroatoms independently selected from the group consisting of S,
O, and N; and the remaining ring atoms are carbon, the radical
being joined to the rest of the molecule via any of the ring atoms,
such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl,
pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,
isoquinolinyl, and the like.
It will be appreciated that aryl and heteroaryl groups can be
unsubstituted or substituted, wherein substitution includes
replacement of one, two, three, or more of the hydrogen atoms
thereon independently with any one or more of the following
moieties including, but not limited to: aliphatic; heteroaliphatic;
aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy;
heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl;
alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy;
alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; --F;
--Cl; --Br; --I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x, wherein each occurrence of R.sub.x
independently includes, but is not limited to, hydrogen, aliphatic,
heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl,
wherein any of the aliphatic, heteroaliphatic, arylalkyl, or
heteroarylalkyl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
Additional examples of generally applicable substituents are
illustrated by the specific embodiments shown in the Examples that
are described herein.
The term "heterocyclic," as used herein, refers to an aromatic or
non-aromatic, partially unsaturated or fully saturated, 3- to
10-membered ring system, which includes single rings of 3 to 8
atoms in size and bi- and tri-cyclic ring systems which may include
aromatic five- or six-membered aryl or aromatic heterocyclic groups
fused to a non-aromatic ring. These heterocyclic rings include
those having from one to three heteroatoms independently selected
from the group consisting of oxygen, sulfur, and nitrogen, in which
the nitrogen and sulfur heteroatoms may optionally be oxidized and
the nitrogen heteroatom may optionally be quaternized. In certain
embodiments, the term heterocyclic refers to a non-aromatic 5-, 6-,
or 7-membered ring or a polycyclic group wherein at least one ring
atom is a heteroatom selected from the group consisting of O, S,
and N (wherein the nitrogen and sulfur heteroatoms may be
optionally oxidized), including, but not limited to, a bi- or
tri-cyclic group, comprising fused six-membered rings having
between one and three heteroatoms independently selected from the
group consisting of the oxygen, sulfur, and nitrogen, wherein (i)
each 5-membered ring has 0 to 2 double bonds, each 6-membered ring
has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double
bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally
oxidized, (iii) the nitrogen heteroatom may optionally be
quaternized, and (iv) any of the above heterocyclic rings may be
fused to an aryl or heteroaryl ring.
The term "alkenyl" as used herein refers to an unsaturated straight
or branched hydrocarbon having at least one carbon-carbon double
bond, such as a straight or branched group of 2-6 or 3-4 carbon
atoms, referred to herein for example as C.sub.2-6alkenyl, and
C.sub.3-4alkenyl, respectively. Exemplary alkenyl groups include,
but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
The term "alkenyloxy" used herein refers to a straight or branched
alkenyl group attached to an oxygen (alkenyl-O). Exemplary alkenoxy
groups include, but are not limited to, groups with an alkenyl
group of 3-6 carbon atoms referred to herein as
C.sub.3-6alkenyloxy. Exemplary "alkenyloxy" groups include, but are
not limited to allyloxy, butenyloxy, etc.
The term "alkoxy" as used herein refers to a straight or branched
alkyl group attached to an oxygen (alkyl-O--). Exemplary alkoxy
groups include, but are not limited to, groups with an alkyl group
of 1-6 or 2-6 carbon atoms, referred to herein as C.sub.1-6alkoxy,
and C.sub.2-C.sub.6alkoxy, respectively. Exemplary alkoxy groups
include, but are not limited to methoxy, ethoxy, isopropoxy,
etc.
The term "alkoxycarbonyl" as used herein refers to a straight or
branched alkyl group attached to oxygen, attached to a carbonyl
group (alkyl-O--C(O)--). Exemplary alkoxycarbonyl groups include,
but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms,
referred to herein as C.sub.1-6alkoxycarbonyl. Exemplary
alkoxycarbonyl groups include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
The term "alkynyloxy" used herein refers to a straight or branched
alkynyl group attached to an oxygen (alkynyl-O)). Exemplary
alkynyloxy groups include, but are not limited to, propynyloxy.
The term "alkyl" as used herein refers to a saturated straight or
branched hydrocarbon, for example, such as a straight or branched
group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as
C.sub.1-6alkyl, C.sub.1-4alkyl, and C.sub.1-3alkyl, respectively.
Exemplary alkyl groups include, but are not limited to, methyl,
ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,
2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl,
2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,
4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,
2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl,
neopentyl, hexyl, etc.
The term "alkylcarbonyl" as used herein refers to a straight or
branched alkyl group attached to a carbonyl group (alkyl-C(O)--).
Exemplary alkylcarbonyl groups include, but are not limited to,
alkylcarbonyl groups of 1-6 atoms, referred to herein as
C.sub.1-6alkylcarbonyl groups. Exemplary alkylcarbonyl groups
include, but are not limited to, acetyl, propanoyl, isopropanoyl,
butanoyl, etc.
The term "alkynyl" as used herein refers to an unsaturated straight
or branched hydrocarbon having at least one carbon-carbon triple
bond, such as a straight or branched group of 2-6, or 3-6 carbon
atoms, referred to herein as C.sub.2-6alkynyl, and
C.sub.3-6alkynyl, respectively. Exemplary alkynyl groups include,
but are not limited to, ethynyl, propynyl, butynyl, pentynyl,
hexynyl, methylpropynyl, etc.
The term "carbonyl" as used herein refers to the radical
--C(O)--.
The term "carboxylic acid" as used herein refers to a group of
formula --CO.sub.2H.
The term "cyano" as used herein refers to the radical --CN.
The term "cycloalkoxy" as used herein refers to a cycloalkyl group
attached to an oxygen (cycloalkyl-O--).
The term "cycloalkyl" as used herein refers to a monocyclic
saturated or partially unsaturated hydrocarbon group of for example
3-6, or 4-6 carbons, referred to herein, e.g., as
C.sub.3-6cycloalkyl or C.sub.4-6cycloalkyl and derived from a
cycloalkane. Exemplary cycloalkyl groups include, but are not
limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or,
cyclopropyl.
The terms "halo" or "halogen" as used herein refer to F, Cl, Br, or
I.
The term "heterocyclylalkoxy" as used herein refers to a
heterocyclyl-alkyl-O-- group.
The term "heterocyclyloxyalkyl" refers to a heterocyclyl-O-alkyl-
group.
The term "heterocyclyloxy" refers to a heterocyclyl-O-- group.
The term "heteroaryloxy" refers to a heteroaryl-O-- group.
The terms "hydroxy" and "hydroxyl" as used herein refers to the
radical --OH.
The term "oxo" as used herein refers to the radical .dbd.O.
The term "connector" as used herein to refers to an atom or a
collection of atoms optionally used to link interconnecting
moieties, such as a disclosed linker and a pharmacophore.
Contemplated connectors are generally hydrolytically stable.
"Treating" includes any effect, e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the
condition, disease, disorder and the like.
"Pharmaceutically or pharmacologically acceptable" include
molecular entities and compositions that do not produce an adverse,
allergic, or other untoward reaction when administered to an
animal, or a human, as appropriate. For human administration,
preparations should meet sterility, pyrogenicity, general safety
and purity standards as required by FDA Office of Biologics
standards.
The term "pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" as used herein refers to any and all
solvents, dispersion media, coatings, isotonic and absorption
delaying agents, and the like, that are compatible with
pharmaceutical administration. The use of such media and agents for
pharmaceutically active substances is well known in the art. The
compositions may also contain other active compounds providing
supplemental, additional, or enhanced therapeutic functions.
The term "pharmaceutical composition" as used herein refers to a
composition comprising at least one compound as disclosed herein
formulated together with one or more pharmaceutically acceptable
carriers.
"Individual," "patient," or "subject" are used interchangeably and
include any animal, including mammals, preferably mice, rats, other
rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or
primates, and most preferably humans. The compounds can be
administered to a mammal, such as a human, but can also be
administered to other mammals such as an animal in need of
veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and
the like), farm animals (e.g., cows, sheep, pigs, horses, and the
like) and laboratory animals (e.g., rats, mice, guinea pigs, and
the like). The mammal treated is desirably a mammal in which
treatment of obesity, or weight loss is desired. "Modulation"
includes antagonism (e.g., inhibition), agonism, partial antagonism
and/or partial agonism.
In the present specification, the term "therapeutically effective
amount" means the amount of the subject compound that will elicit
the biological or medical response of a tissue, system, animal, or
human that is being sought by the researcher, veterinarian, medical
doctor, or other clinician. The compounds are administered in
therapeutically effective amounts to treat a disease.
Alternatively, a therapeutically effective amount of a compound is
the quantity required to achieve a desired therapeutic and/or
prophylactic effect, such as an amount which results in weight
loss.
The term "pharmaceutically acceptable salt(s)" as used herein
refers to salts of acidic or basic groups that may be present in
compounds used in the present compositions. Compounds included in
the present compositions that are basic in nature are capable of
forming a wide variety of salts with various inorganic and organic
acids. The acids that may be used to prepare pharmaceutically
acceptable acid addition salts of such basic compounds are those
that form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, including but not limited to
malate, oxalate, chloride, bromide, iodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds
included in the present compositions that are acidic in nature are
capable of forming base salts with various pharmacologically
acceptable cations. Examples of such salts include alkali metal or
alkaline earth metal salts and, particularly, calcium, magnesium,
sodium, lithium, zinc, potassium, and iron salts. Compounds
included in the present compositions that include a basic or acidic
moiety may also form pharmaceutically acceptable salts with various
amino acids. The compounds of the disclosure may contain both
acidic and basic groups; for example, one amino and one carboxylic
acid group. In such a case, the compound can exist as an acid
addition salt, a zwitterion, or a base salt.
The compounds of the disclosure may contain one or more chiral
centers and/or double bonds and, therefore, exist as stereoisomers,
such as geometric isomers, enantiomers or diastereomers. The term
"stereoisomers" when used herein consist of all geometric isomers,
enantiomers or diastereomers. These compounds may be designated by
the symbols "R" or "S," depending on the configuration of
substituents around the stereogenic carbon atom. Various
stereoisomers of these compounds and mixtures thereof are
encompassed by this disclosure. Stereoisomers include enantiomers
and diastereomers. Mixtures of enantiomers or diastereomers may be
designated "(.+-.)" in nomenclature, but the skilled artisan will
recognize that a structure may denote a chiral center
implicitly.
The compounds of the disclosure may contain one or more chiral
centers and/or double bonds and, therefore, exist as geometric
isomers, enantiomers or diastereomers. The enantiomers and
diastereomers may be designated by the symbols "(+)," "(-)." "R" or
"S," depending on the configuration of substituents around the
stereogenic carbon atom, but the skilled artisan will recognize
that a structure may denote a chiral center implicitly. Geometric
isomers, resulting from the arrangement of substituents around a
carbon-carbon double bond or arrangement of substituents around a
cycloalkyl or heterocyclic ring, can also exist in the compounds.
The symbol denotes a bond that may be a single, double or triple
bond as described herein. Substituents around a carbon-carbon
double bond are designated as being in the "Z" or "E" configuration
wherein the terms "Z" and "E" are used in accordance with IUPAC
standards. Unless otherwise specified, structures depicting double
bonds encompass both the "E" and "Z" isomers. Substituents around a
carbon-carbon double bond alternatively can be referred to as "cis"
or "trans," where "cis" represents substituents on the same side of
the double bond and "trans" represents substituents on opposite
sides of the double bond. The arrangement of substituents around a
carbocyclic ring can also be designated as "cis" or "trans." The
term "cis" represents substituents on the same side of the plane of
the ring and the term "trans" represents substituents on opposite
sides of the plane of the ring. Mixtures of compounds wherein the
substituents are disposed on both the same and opposite sides of
plane of the ring are designated "cis/trans."
The term "stereoisomers" when used herein consist of all geometric
isomers, enantiomers or diastereomers. Various stereoisomers of
these compounds and mixtures thereof are encompassed by this
disclosure.
Individual enantiomers and diasteriomers of the compounds can be
prepared synthetically from commercially available starting
materials that contain asymmetric or stereogenic centers, or by
preparation of racemic mixtures followed by resolution methods well
known to those of ordinary skill in the art. These methods of
resolution are exemplified by (1) attachment of a mixture of
enantiomers to a chiral auxiliary, separation of the resulting
mixture of diastereomers by recrystallization or chromatography and
liberation of the optically pure product from the auxiliary, (2)
salt formation employing an optically active resolving agent, (3)
direct separation of the mixture of optical enantiomers on chiral
liquid chromatographic columns or (4) kinetic resolution using
stereoselective chemical or enzymatic reagents. Racemic mixtures
can also be resolved into their component enantiomers by well known
methods, such as chiral-phase gas chromatography or crystallizing
the compound in a chiral solvent. Stereoselective syntheses, a
chemical or enzymatic reaction in which a single reactant forms an
unequal mixture of stereoisomers during the creation of a new
stereocenter or during the transformation of a pre-existing one,
are well known in the art. Stereoselective syntheses encompass both
enantio- and diastereoselective transformations. For examples, see
Carreira and Kvaerno, Classics in Stereoselective Synthesis,
Wiley-VCH: Weinheim, 2009.
The compounds disclosed herein can exist in solvated as well as
unsolvated forms with pharmaceutically acceptable solvents such as
water, ethanol, and the like. In one embodiment, the compound is
amorphous. In one embodiment, the compound is a polymorph. In
another embodiment, the compound is in a crystalline form.
Also embraced are isotopically labeled compounds which are
identical to those recited herein, except that one or more atoms
are replaced by an atom having an atomic mass or mass number
different from the atomic mass or mass number usually found in
nature. Examples of isotopes that can be incorporated into the
compounds include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, sulfur, fluorine and chlorine, such as .sup.2H,
.sup.3H, .sup.13C .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, .sup.10B, and .sup.36Cl,
respectively. For example, a compound may have one or more H atom
replaced with deuterium.
Certain isotopically-labeled disclosed compounds (e.g., those
labeled with .sup.3H and .sup.14C) are useful in compound and/or
substrate tissue distribution assays. Tritiated (i.e., .sup.3H) and
carbon-14 (i.e., .sup.14C) isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium (i.e., .sup.2H) may afford
certain therapeutic advantages resulting from greater metabolic
stability (e.g., increased in vivo half-life or reduced dosage
requirements) and hence may be preferred in some circumstances.
Isotopically labeled compounds can generally be prepared by
following procedures analogous to those disclosed in the Examples
herein by substituting an isotopically labeled reagent for a
non-isotopically labeled reagent.
The term "prodrug" refers to compounds that are transformed in vivo
to yield a disclosed compound or a pharmaceutically acceptable
salt, hydrate or solvate of the compound. The transformation may
occur by various mechanisms (such as by esterase, amidase,
phosphatase, oxidative and or reductive metabolism) in various
locations (such as in the intestinal lumen or upon transit of the
intestine, blood, or liver). Prodrugs are well known in the art
(for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug
Discovery 2008, 7, 255). For example, if a compound or a
pharmaceutically acceptable salt, hydrate, or solvate of the
compound contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a group such as (C.sub.1-8)alkyl,
(C.sub.2-12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4
to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to
10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon
atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
Similarly, if a compound contains an alcohol functional group, a
prodrug can be formed by the replacement of the hydrogen atom of
the alcohol group with a group such as
(C.sub.1-6)alkanoyloxymethyl, 1-((C.sub.1-6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-6)alkanoyloxy)ethyl
(C.sub.1-6)alkoxycarbonyloxymethyl,
N--(C.sub.1-6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-6)alkanoyl, .alpha.-amino(C.sub.1-4)alkanoyl, arylacyl and
.alpha.-aminoacyl, or .alpha.-aminoacyl-.alpha.-aminoacyl, where
each .alpha.-aminoacyl group is independently selected from the
naturally occurring L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
If a compound incorporates an amine functional group, a prodrug can
be formed, for example, by creation of an amide or carbamate, an
N-acyloxyakyl derivative, an (oxodioxolenyl)methyl derivative, an
N-Mannich base, imine, or enamine. In addition, a secondary amine
can be metabolically cleaved to generate a bioactive primary amine,
or a tertiary amine can be metabolically cleaved to generate a
bioactive primary or secondary amine. For examples, see Simplicio,
et al., Molecules 2008, 13, 519 and references therein.
INCORPORATION BY REFERENCE
All publications and patents mentioned herein, including those
items listed below, are hereby incorporated by reference in their
entirety for all purposes as if each individual publication or
patent was specifically and individually incorporated by reference.
In case of conflict, the present application, including any
definitions herein, will control.
EXAMPLES
The compounds described herein can be prepared in a number of ways
based on the teachings contained herein and synthetic procedures
known in the art. In the description of the synthetic methods
described below, it is to be understood that all proposed reaction
conditions, including choice of solvent, reaction atmosphere,
reaction temperature, duration of the experiment and workup
procedures, can be chosen to be the conditions standard for that
reaction, unless otherwise indicated. It is understood by one
skilled in the art of organic synthesis that the functionality
present on various portions of the molecule should be compatible
with the reagents and reactions proposed. Substituents not
compatible with the reaction conditions will be apparent to one
skilled in the art, and alternate methods are therefore indicated.
The starting materials for the examples are either commercially
available or are readily prepared by standard methods from known
materials.
At least some of the compounds identified as "Intermediates" herein
are contemplated as active ingredients.
For ease of reading, intermediates are provided in Table 3. At
least some of the compounds identified as "Intermediates" herein
are contemplated as compounds of the invention. Example compounds
are provided in Table 4.
TABLE-US-00003 TABLE 3 INTERMEDIATES INDEX Sr. No. Structure
Compound Name Cmpd. Code Tryptase targets Method-D 1. ##STR00021##
(E)-1-(4-(3-(aminomethyl)phenyl)piperidin-1-
yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en- 1-one T-24 mono methoxy
2. ##STR00022## (4-(3-(aminomethyl)phenyl)piperidin-1-
yl)(5-hydroxy-1H-indol-2-yl)methanone Target-31a 3. ##STR00023##
(4-(3-(aminomethyl)phenyl)piperidin-1-yl)(2-
bromobenzo[b]thiophen-4-yl)methanone Target-37a 4. ##STR00024##
(4-(3-(aminomethyl)phenyl)piperidin-1-yl)
(benzofuran-4-yl)methanone Target-38H 5. ##STR00025##
1-(4-(3-(aminomethyl)phenyl)piperidin-1-yl)-
2-(3-fluoro-4-hydroxyphenyl)ethanone Target-54a 6. ##STR00026##
(4-(3-(aminomethyl)phenyl)piperidin-1-
yl)(4-bromobenzo[b]thiophen-2- yl)methanone Target-56a
TABLE-US-00004 TABLE 4 EXAMPLES OF HOMODIMERS Sr. Cmpd. No. Code
Structure 7. Formed form Target- 46 ##STR00027## 8. Formed form
Target- 47 ##STR00028## 9. Formed form Target- 48 ##STR00029## 10.
Formed form Target- 47- Vinyl ##STR00030##
Example 1
Evaluation of Inhibition of Tryptase Activity by Multimers
Stock solutions of recombinant human tryptase, beta, from lung
(Promega: catalog number G5631, or Enzo Life Sciences: catalog
number BML-SE418) were made at 30 .mu.M, in solution with 50 .mu.M
heparin sulfate and 500 mM NaCl. Multimer tryptase inhibitor stock
solutions were made at 50 mM in DMSO. Drug plates were made at
5.times. the final concentration in assay buffer (50 mM HEPES, 150
mM NaCl, 100 .mu.M EDTA, pH 7.4, 0.02% Tween-20). A final
concentration of 1 nM tryptase was used. When required, drugs were
diluted in assay buffer immediately before use in 10-fold serial
dilutions. After the indicated incubation time, the
multimer-tryptase solution at 5.times. concentration, was diluted
into assay buffer containing a final concentration of 200 .mu.M
N-tert-butoxycarbonyl-Gln-Ala-Arg-AMC
HBr[AMC=7-amino-4-methylcoumarin] (Boc-Gln-Ala-Arg-AMC; Enzo Life
Sciences: catalog number BML-P237) to a final volume of 50 .mu.l in
black opaque round bottom 96 well plates (Corning, catalog number
3792). The release of fluorescent AMC was immediately measured
every 60 seconds over 30-60 minutes at an excitation wavelength of
367 nm, monitoring emission at 468 nm on a Spectramax M5 (Molecular
Devices) microplate reader. The Softmax Pro (Molecular Devices) and
Graphpad prism software were used to determine V.sub.max, and
concentration-response curve IC.sub.50s, respectively.
Example 2
Evaluation of Inhibition of Ribosomal Protein Synthesis by
Multimers
Monomers with the potential to form heterodimers were evaluated in
an in vitro Transcription and Translation assay (TnT assay) using
the commercially available E. coli S30 Extract System for Circular
DNA kit (Promega Catalog #L1020) according to the manufacturers
instructions with minor modifications. Monomers were tested
independently to determine individual IC.sub.50 values. Pairs of
monomers with the potential to form heterodimers were assayed at
concentrations that ranged about their individual IC.sub.25 values.
Each reaction uses 2 .mu.l (250 ng/.mu.l) of the pBESTluc.TM. DNA
based circular luciferase plasmid (Promega Catalog #L492A), with 4
.mu.l of complete amino acid mix (Promega Catalog #L4461), 13 of
S30 Premix Without Amino Acids (Promega Catalog #L512A), 5 .mu.l of
S30 Extract (Promega Catalog #L464A), monomers at the appropriate
concentration, and nuclease free water in a total volume of 35 al.
Assays were carried out in Costar 96 well white round bottom
plates. Assay plates were setup with a master mix consisting of S30
extract and water, followed by the addition of compound, with the
final addition of a master mix consisting of the plasmid, amino
acid mix, and the S30 Premix. Plates were incubated at 37.degree.
C. for one hour followed by addition of 35 .mu.l of the Bright-Glo
Luciferase Reagent (Promega Catalog #E2620). After removal of 35
.mu.l of the reaction mixture, the luminescence was recorded
immediately in the Spectramax M5 plate reader (Molecular Devices).
The data was plotted to generate dose-response curves using
GraphPad Prism.
As indicated below, IC.sub.50 ranges are provided for various
exemplary monomers. For the names of the monomers, the prefix
"Target," as used elsewhere in the Examples, has been shortened to
"T." For example, "Target-14" has been shortened to "T14." "A"
refers to an IC.sub.50 range of 0.1 nM to 1 .mu.M, "B" refers to an
IC.sub.50 range of 1 .mu.M to 10 .mu.M, and "C" refers to an
IC.sub.50 range of 10 .mu.M to 65 .mu.M.
Results
Group A: T52; T148; T120F; T52SPIRO; T129SPIRO; T46; T129; T138;
T129Smethyl;
T130; T49; T137; T47; T11SILYL.
Group B: T149; T47vinyl; T122; T48.
Group C: T152NMethyl; T35 Silyl; T32Silyl; T152; T61Silyl.
Example 3
Synthesis of Dimethyl (Aryl) Silanols
Method G
Desired halo aryl carboxylic acids were first coupled with
tert-butyl 3-(piperidin-4-yl) benzylcarbamate and coupled product
was reacted with 1,2-diethoxy-1,1,2,2-tetramethyldisilane to get
ethoxydimethyl(Aryl)silanes, which upon treatment with acetic acid
and subsequent treatment with TFA resulted in the title compounds.
These compounds as well as their N-Boc precursors were found to be
in the form of mixture of monomer and dimer in HPLC/LCMS
analysis.
Vinylic analogue of this compound was synthesized by reaction of
Boc De-protected B-47 with dimethyl ethoxy vinyl silane in presence
of Pd (II) acetate & Tri (O-tolyl) phosphine in DMF using
sodium acetate as a base (Scheme-2).
##STR00031##
##STR00032## Step-1
To a stirred solution of carboxylic acid in DCM or DMF was added
and EDCI, HOBT (in some cases) & DMAP or DIPEA. The solution
was stirred for 15 min. at 0.degree. C. followed by addition of
desired tert-butyl 3-(piperidin-4-yl) benzylcarbamate. Stirring was
continued at room temperature and reaction was monitored by LCMS
till maximum, starting materials were consumed. Reaction mixture
was then quenched with Water and aq. layer was extracted with
dichloromethane and combined organic layers were dried over sodium
sulphate and concentrated under vacuum to afford the product which
was used for next step without purification. The details of
compounds synthesized by above method are as below.
Coupled products were purified by column chromatography over silica
gel using methanol (0-1%) in dichloromethane. Details of the
compounds synthesized are as below.
TABLE-US-00005 TABLE 6 REACTION CONDITIONS & ANALYTICAL DATA
Comp. Brief Reaction No. Structure conditions Analytical data B-46
##STR00033## tert-butyl 3-(piperidin-4-yl) benzyl carbamate (1
eq.), EDCI (1.5 eq.), DMAP(1.1 eq) HOBT (1.1 eq)DCM, RT, 2 h,
Yield:- 51.53% Mol. Wt:- 529.49 M.I. Peak observed:- 531.30 HPLC
purity:- 92.16% B-47 ##STR00034## Same as above Yield:- 60.78% Mol.
Wt:- 487.43 M.I. Peak observed:- 509.35 (M + Na), HPLC purity:-
91.37% B-48 ##STR00035## Same as above Yield:- 88.20% Mol. Wt:-
487.43 M.I. Peak observed:- 489.25 HPLC purity:- 97.88% B-49
##STR00036## Same as above Yield:-% 50% Mol. Wt:- 529.49 M.I. Peak
observed:- 553.05(M + Na)
Step-2 & 3
Stirred suspension of Coupled products from step-1 was degassed
with argon and N-methyl pyrrolidine, palladium chloride,
di-isopropylethylamine & 1,2,diethoxy-1,1,2,2, tetramethyl
silane was added to it. Reaction mass was heated to
.about.60.degree. C. and reaction monitored by LCMS till maximum
starting material was consumed. There after acetonitrile, 1N aq.
acetic acid and 2-(dimethyl-amino)-ethane thiol hydrochloride was
added and reaction mass stirred for 2 hrs at room temperature.
Reaction mass was then diluted with water, extracted with ethyl
acetate and ethyl acetate extracts were concentrated in vacuum
after drying over sodium sulfate to get the crude products which
were partly purified by column chromatography (Purity .about.50% by
HPLC) and used for next step.
TABLE-US-00006 TABLE 7 REACTION CONDITIONS & ANALYTICAL DATA
Comp. Brief Reaction No. Structure conditions Analytical data C-46
##STR00037## Step-2 NMP (10 vol), PdCl2(0.1 eq), DTBP BP(0.2 eq),
DIPEA(6 eq), 1,2,diethoxy-1,1,2,2, tetramethyl silane (3 eq),
60.degree. C. 18 hrs, Step-3 Acetonitrile (10 vol) 1N aq. acetic
acid (20 Vol), 2- (Dimethyl amino) ethane thiol hydrochloride (0.25
eq.) RT, 2 hrs, Yield:- 33% (Crude) Mol. Wt:- 1031.48 (Dimer)
524.22(monomer) M.I. Peak observed- De-Boc Dimer -831.10 C-47
##STR00038## Same as above Yield:- 41% Mol. Wt:- 947.36 (Dimer)
482.36 (monomer) M.I. Peak observed- Monomer:- 483.45 De-Boc
Dimer:- 747.40 C-48 ##STR00039## Same as above Yield:- 30% Mol.
Wt:- 947.36(Dimer) 482.36 (monomer) M.I. Peak observed- De-Boc
Dimer-747.25 C-49 ##STR00040## Same as above Yield:- 30% Mol. Wt:-
1031.48(Dimer) 524.75 (monomer) M.I. Peak observed- De-Boc monomer
425.1 De-Boc Dimer-831.3
Step-4
Products from step-3 were stirred with trifluoroacetic acid in
dichoromethane at room temperature and reactions were monitored by
TLC & LCMS till maximum, starting materials were consumed.
Reaction mass was concentrated in vacuum to remove excess trifluoro
acetic acid and dichlorimethane. Crude products obtained were
purified by reverse phase preparative HPLC. The pure fraction of
mobile phase was lyophilized to get the products as TFA salts.
TFA salts were converted to hydrochloride salts by stirring with 2N
HCl for 30 min under nitrogen atmosphere followed by
lyophilization.
Compounds were found to be mixture of monomer & dimer as per
HPLC as well as NMR data, in all the cases.
TABLE-US-00007 TABLE 8 REACTION CONDITIONS & ANALYTICAL DATA
Comp. Brief Reaction No. Structure conditions Analytical data
Target- 46 ##STR00041## DCM, TFA(3.3 Vol), RT, 3 Hrs. Preparative
HPLC. Isolated as TFA salt. Yield:- 12% Mol. Wt:- 831.25Dimer
424.63-Monomer M.I. Peak observed (LSMS):- 446.90(Monomer + Na)
831.20(Dimer) HPLC Purity:- 36.15% monomer, 63.84% dimer .sup.1H
NMR CD3OD:- 3.4(d, 6H), 1.60-1.96 (m, 4H), 2.80-2.99(m, 4H),
4.09-4.11 (d, 2H), 4.59(s, 1H), 7.25-7.45 (m, 4H), 7.59-7.69(m,
2H), 7.96-7.99(m, 2H). Target- 47 ##STR00042## Same as above.
Preparative HPLC. Isolated as TFA salt. Yield:- 10% Mol. Wt:-
382.57 (monomer) Dimer-747.13 M.I. Peak observed: 383.45 HPLC
Purity:- 91.53 monomer, 6.4% dimer .sup.1H NMR ACN-d3:D2O:- 0.27(s,
12H), 1.18-1.30(m, 2H), 1.43- 1.50(m, 2H), 1.67-1.70(d, 2H),
1.78-1.81(d, 2H), 1.92-1.96 (m, 2H), 3.71(s, 2H), 3.81-3.83 (m,
2H), 3.94-4.02(m, 6H), 4.57(t, 2H), 7.14-7.53(m, 17H). Target- 48
##STR00043## Same as above. Isolated as TFA salt. Yield:- 11% Mol.
Wt:- 382.57 (monomer) 747.13 (Dimer) M.I. Peak observed: Monomer:-
383.05, Dimer:-747.20 HPLC Purity:- Monomer:-31.10%, Dimer:- 67.89%
.sup.1H NMR ACN:-.0.289(s, 6H), 1.270-1.321(m, 2H), 1.423-1.507 (m,
2H), 1.679-1.708(d, 2H, J = 11.6 Hz), 1.760-1.791 (d, 1H, J = 12.4
Hz), 2.621 (t, 1H), 3.118- 3.085(m, 1H), 3.785-3.652 (m, 2H), 3.952
(s, 2H), 4.593-4.022 (d, 1H), 7.142-7.318 (m, 5H), 7.488- 7.409 (d,
1H), 7.504-7.540 (d, 1H), 7.861(s, 3H). Target- 49 ##STR00044##
Same as above. Isolated as TFA salt. Yield:- 25% Mol. Wt:- 425.63
(monomer) 831.25 (Dimer) M.I. Peak observed: Monomer:-424.95
Dimer:- 831.25 HPLC Purity:- Monomer:-24.56 Dimer:-73.69 .sup.1H
NMR ACN:- 0.42-0.46(d, 6H), 1.45-1.72(m, 4H), 2.75-2.99(m, 3H),
3.42-3.44(m, 1H), 4.00- 4.06(d, 2H), 4.76-4.79(m, 1H), 7.22-7.56(m,
7H), 7.97-8.02(m, 1H).
Step-5 & 6
Compound B-47 was deprotected using TFA in DCM as per method
described earlier and deprotected product was heated with
dimethylvinylethoxysilane Pd(II)acetate, tri(O-tolyl)phosphine in
dimethyl formamide-Water (2:1) using sodium acetate as base.
Reaction was monitored by LCMS. After consumption of starting,
reaction mass was cooled to room temp., quenched with water,
extracted with ethyl acetate and ethyl acetate extract was
concentrated in vacuum after drying over sodium sulfate to get the
crude product which was purified by reverse phase preparative HPLC.
Product was isolated as TFA salt.
TABLE-US-00008 TABLE 9 REACTION CONDITIONS & ANALYTICAL DATA
Target- 47- Vinyl ##STR00045## 1):- B-47, DCM, TFA(3.3 Vol), RT, 3
Hrs, 80% 2):- Dimethylvinylethoxy silane (4 eq), Pd(II)acetate (30%
bywt), Tri(O- tolyl) phosphine Mol. Wt:- 408.61monomer Dimer-799.20
M.I. Peak observed :- 431.05(monomer Na+), 800(Dimer) HPLC Purity:-
96.44% .sup.1H NMR DMSO-d6:- 0.242(s, 6H), 1.386-1.465(m, 2H),
1.715-1.777 (t, 2H), 2.605-2.668(t, 1H), 2.735- 2.764 (t, 1H),
3.064-3.125(t, 1H), (15% by wt) 3.692-3.680 (m, 2H), 3.995-4.008
DMF(10 Vol), sodium (d, 2H, J = 5.2 Hz), 4.063-4.096 acetate(5 eq),
80.degree. C. 2 (d, 1H, J = 13.2 Hz), 4.545-4.575 hrs. Prep HPLC.
Isolated (1H, d, J = 12 Hz), 6.459-6.508 as TFA salt. 10%. (d, 1H,
J = 19.6 Hz), 6.941-6.989 (d, 1H, J = 19.2 Hz), 7.166-7.380 (m,
8H), 8.149(bs, 3H)
Example 4
Synthesis of Tryptase Inhibitors with Silanols Functionality
Seventeen final targets with Silanol functionality were
synthesized. These compounds were synthesized by three different
approaches as given below.
Approach-1:--
Desired halo aryl carboxylic acids were first coupled with
protected 4-(3-Aminomethyl phenyl) piperidine or 5-Aminomethyl
Spiro [benzofuran-3,4'-piperidine]. Coupled product was reacted
with 1,2-diethoxy-1,1,2,2-tetramethyldisilane to get
ethoxydimethyl(Aryl)silanes, which upon treatment with acetic acid
and subsequent deprotection afforded in the title compounds. 11
compounds were synthesized from Approach-1.
General Synthetic Scheme:
##STR00046##
Approach-2:--
Desired halo aryl carboxylic acids were esterified and converted to
silanols as mentioned above and subsequently hydrolyzed to
carboxylic acid with dimethyl silanols functionality as mixture of
monomer and dimer which was coupled with appropriate Core shown in
the Synthetic Scheme Followed by deprotection. Most of the silanols
were isolated as mixture of monomer and dimer.
The details of intermediates (A) sourced/synthesised as per
literature methods/synthesised by developed adapted methods are
given below. 4 compounds were synthesized from Approach-2
General Synthetic Scheme:
##STR00047##
Approach-3:--
Suitably substituted dimethyl (aryloxymethyl) silanols were
synthesized by alkylation of Aryl hydroxyl carboxylates and
subsequent hydrolysis of ester and coupled with the desired
protected core. Deprotection on the amino methyl functionality
afforded corresponding carboxylic acids with O-silanol. 2 compounds
were synthesized from Approach-3.
General Synthetic Scheme:
##STR00048##
The details of intermediates (A) sourced/synthesised as per
literature methods/synthesised by adapted methods are given
below.
TABLE-US-00009 Comp. No. Structure A1-11 ##STR00049## A1-32
##STR00050## A1-35 ##STR00051## A1-52 ##STR00052## A1-62
##STR00053## A1-120F ##STR00054## A1-122 ##STR00055## A1-129
##STR00056## A1-129 S-Me ##STR00057## A1-137 ##STR00058## A1-138
##STR00059## A1-148 ##STR00060## A1-149 ##STR00061## A1-152
##STR00062##
Synthesis of 4-((hydroxyl dimethyl silyl) methoxy) benzoic acid
(A1-137)
##STR00063##
Experimental Procedures
Step-1
A stirred solution of methyl-4-hydroxy benzoate (1 g, 6.58 mmol)
and potassium carbonate (2.72 g, 19.7 mmol) in acetone (30 mL)
stirred at room-temperature for 15 min. and charged with
chloromethyl dimethyl methoxy silane (1.4 mL, 9.8 mmol) and heated
to 60.degree. C. for 72 hr. The solvent was concentrated in vacuo
and the residue was diluted with water (20 mL) and extracted with
ethyl acetate (3.times.25 mL). The combined organic layer was
washed with brine (2.times.20 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo resulting in a crude product
which was purified by column chromatography to get a colorless
oil.
Yield: 770 mg, 46.10%
HPLC purity: 95.35%,
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.24 (d, J=12 Hz, 6H),
2.74 (s, 3H), 3.60 (s, 2H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz, 2H),
7.98 (d, J=8.4 Hz, 2H).
Step-2
A stirred solution of step-1 product (770 mg, 3.0 mmol) in
THF/water (1:1) (20 mL) was charged with lithium hydroxide (109 mg,
4.5 mmol) and stirred at room-temperature for 24 hrs. The solvent
was concentrated in vacuo and residue was acidified to pH=2 using
1N KHSO.sub.4 and was extracted with ethyl acetate (2.times.25 mL).
The combined organic layer was washed with brine (2.times.20 mL),
dried over sodium sulfate, filtered, and concentrated in vacuo to
get a yellow solid (Qty-540 mg)
Yield: 540 mg, 78.83%.
Mol Wt: 226.30
MS (ES+): in/z=226.10 [MH.sup.+], (ES-)=225.44 [MH.sup.-]
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.9 (bs, 1H), 7.49
(t, J=5.4 Hz, 2H), 7.39 (t, J=7.9 Hz, 1H), 7.21 (dd, J=8.0, 2.9 Hz,
1H), 3.62 (d, J=22.5 Hz, 2H), 0.18 (s, 6H).
Synthesis of 3-((hydroxyl dimethyl silyl) methoxy) benzoic acid
(A1-138)
##STR00064##
Experimental Procedures
Step-1
A stirred solution of methyl-3-hydroxy benzoate (1 g, 6.578 mmol)
in acetone (30 mL) and potassium carbonate (2.72 g, 19.7 mmol) was
stirred at room-temperature for 15 min and then charged with
chloromethyl dimethyl methoxy silane (1.4 mL, 9.8 mmol) and heated
to 60.degree. C. for 72 hrs. The solvent was concentrated in vacuo
and diluted with water (20 mL) and extracted with ethyl acetate
(3.times.25 mL). The combined organic layer was washed with brine
(2.times.20 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo resulting in a crude product that was
purified by column chromatography to get the colorless oil.
(Qty-1.03 g),
Yield: 1.03 g, 67%
HPLC purity: 99.25%,
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.61 (d, J=3.4 Hz, 1H),
7.33 (t, J=8.0 Hz, 1H), 7.27-7.23 (m, 1H), 7.14 (d, J=8.0 Hz, 1H),
3.92 (s, 3H), 3.59 (s, 3H), 0.23 (d, J=11.5 Hz, 6H).
Step-2
A stirred solution of step-1 product (1.03 g, 4.5 mmol) in
THF/water (1:1) (20 mL) was charged with lithium hydroxide (145 mg,
6.04 mmol) and stirred at room-temperature for 24 hr. The solvent
was concentrated in vacuo and residue was acidified to pH=2 using
1N KHSO.sub.4 and was extracted with ethyl acetate (2.times.25 mL).
The combined organic layer was washed with brine (2.times.20 mL),
dried over sodium sulfate, filtered, and concentrated in vacuo
resulting in a yellow solid as crude product. (Qty-440 mg)
Yield: 440 mg, 48.83%
Mol Wt-226.30,
MS (ES-): m/z=225.18 [MH.sup.-]
The detailed description of the amide intermediates and Final
Targets synthesized by three different approaches is given
below.
Approach-1
Step-1
Coupling of the aryl bromo carboxylic acids (A1) was carried out
with appropriate protected core as shown in the synthetic scheme as
per conditions mentioned in the table below.
TABLE-US-00010 Comp. Brief Reaction No. Structure conditions
Analytical data A-62 ##STR00065## tert-butyl-3-(piperidin-4-yl)
benzyl carbamate, (1.2 eq.), EDCI (1.5 eq.) DMAP (0.5 eq.), DCM (5
ml) R.T. 12 h; Yield: 59% Mol. Wt.: 549.5 MS (ES+): m/z = 549/551.4
[MH.sup.+], A-35 ##STR00066## tert-butyl-3-(piperidin-4-yl) benzyl
carbamate, (1.2 eq.), EDCI (1.5 eq.) DMAP (0.5 eq.), DCM R.T. 15 h;
Mol. Wt.: 549.5 MS (ES+): m/z = 549/551.3 [MH.sup.+], Yield:- 76%
A-152 ##STR00067## tert-butyl-3-(piperidin-4-yl) benzyl carbamate,
(1 eq.), EDCI (1.5 eq.) HOBt (1.5 eq.), DIEA (2 eq.) DMF (15 vol)
R.T. 15 h; Mol. Wt.: 512.44 MS (ES+): m/z = 512/514.1 [MH.sup.+]
Yield:- 55% A-32 ##STR00068## Tert-Butyl 3-(piperidin-4-yl) benzyl
carbamate, (1 eq.), EDCI (1.5 eq.) HOBt (1.5 eq.), DIEA (2 eq.) DMF
(15 vol) R.T. 15 h; Mol. Wt.: 512.44 MS (ES+): m/z = 512/514.4
[MH.sup.+] Yield;- 62% A-152 N- Methyl ##STR00069## Synthesized by
reacting A-152 with methyl iodide (3 eq.) and potassium carbonate
(1.5 eq.) in DMF (50 vol) at R.T. for 2 hrs, Purified by column
chromatography over silica gel after quenching with water and
isolation by extraction with DCM. Yield:- 97% Mol. Wt.: 526.47 MS
(ES+): m/z = 526/528.2 [MH.sup.+] Yield:- 97% 129 S-Me ##STR00070##
tert-butyl-I3-(piperidin-4-yl) benzyl carbamate, (1 eq.), EDCI (1.5
eq.) HOBt (1.5 eq.), DIEA (2.5 eq.) DMF (15 vol) R.T. 15 h; Mol.
Wt.: 518.07 MS (ES+): m/z = 518/520.1 [MH.sup.+] Yield:- 38% A-11
##STR00071## A-148 ##STR00072## tert-butyl-I-3-(piperidin-4-yl)
benzyl carbamate, (1 eq.), EDCI (1.5 eq.) DMAP (1.2 eq.), DCM (25
vol) R.T. 15 h; Yield:- 91%, Mol. Wt:-513.42 MS (ES+): m/z =
513/515.00 [MH.sup.+] A-149 ##STR00073## tert-butyl-3-(piperidin-4-
yl)benzyl carbamate (1 eq.), EDCI.HCl (1.5 eq.), DMAP (1.2 eq.),
DCM(20 vol), RT, 4 h, Purified by column chromatography Yield:-
71%, Mol. Wt:- 529.49 MS (ES+): m/z = 529/531 [MH.sup.+] A-120F
##STR00074## 2,2,2-trifluoro-N-(4-fluoro-3- (piperidin-4-
yl)benzyl)acetamide (1.3 eq.), EDCI.HCl (1.5 eq.), DMAP (2 eq.),
DCM(20 vol), RT, 4 h, Yield:- 80%, Mol. Wt:- 537.34 MS (ES+): m/z =
536/538.20 [MH.sup.+] A-129 ##STR00075##
tert-butyl3-(piperidin--4-yl) benzyl carbamate (1.3 eq.), 3- bromo
benzoic acid, EDCI.HCl (1.5 eq.), DMAP (2 eq.), DCM(20 vol), RT, 4
h, Yield:- 80%, Mol. Wt:- 473.40 MS (ES+): m/z = 495.95/497.95
[MH.sup.+ + Na]
Step-2
Stirred suspension of coupled products from step-1 in N-methyl
pyrrolidine was degassed with argon and, palladium chloride,
di-isopropyl ethyl amine, and 1,2-diethoxy-1,1,2,2, tetra methyl
silane were added to it. Reaction mixture was heated to
.about.60.degree. C. and reaction monitored by LCMS till most of
the starting material was consumed. There after acetonitrile, 1N
aq. acetic acid and 2-(dimethyl amino) ethane thiol hydrochloride
was added and reaction mixture stirred for 2 hr at room
temperature. Reaction mixture was diluted with water, filtered
through celite, extracted with ethyl acetate and the combined ethyl
acetate extracts were dried over sodium sulfate, filtered, and
concentrated in vacuo to get the crude products which were
sufficiently pure to be used for silylation.
The details of the compounds are given below.
TABLE-US-00011 Comp. Brief Reaction No. Structure conditions
Analytical data B-62-Si ##STR00076## 1-2 diethoxy 1,1,2,2, tetra
methyl disilane (3 eq.) PdPPh.sub.3 (0.05 eq), potassium acetate (4
eq.), NMP (75 vol), 140.degree. C., Microwave 10 min. Reaction mass
quenched with water extracted with ethyl acetate and purified over
neutral silica to get the product Yield:- 7.5% Mol. Wt.: 544.28 MS
(ES+): m/z = 567 [MH.sup.+ + Na] B-35-Si ##STR00077## 1-2 diethoxy
1,1,2,2, tetra methyl disilane (3 eq.) PdPPh.sub.3 (0.05 eq),
potassium acetate (4 eq.), NMP (75 vol), 140.degree. C., Microwave
10 min. Reaction mass quenched with water extracted with ethyl
acetate and purified over neutral silica to get the product Yield:-
10% Mol. Wt.: 544.28 MS (ES+): m/z = 567 [MH.sup.+ + Na] B-152 N-
Methyl ##STR00078## 1-methyl-2-pyrrolidinone (30 vol.),
2-(di-t-butylphosphino) biphenyl (0.1 eq.) and DIEA (3.0 eq.).
PdCl.sub.2 (0.05 eq.) 1,2- diethoxy-1,1,2,2-tetramethyl disilane
(1.1 eq.) 60.degree. C. 10 h. White solid; Yield: 38% Mol. Wt.:
521.72 MS (ES+): m/z = 522 [MH.sup.+] B-152 ##STR00079##
1-methyl-2-pyrrolidinone (30 vol.), 2-(di-t-butylphosphino)
biphenyl (0.1 eq.) and DIEA (3.0 eq.). PdCl.sub.2(0.05 eq.) 1,2-
diethoxy-1,1,2,2-tetramethyl disilane (1.1 eq.) 60.degree. C. h.
White solid; Yield: 33% Mol. Wt.: 507.70 MS (ES+): m/z = 508
[MH.sup.+] B-32 Si ##STR00080## 1-methyl-2-pyrrolidinone (30 vol.),
2-(di-t-butylphosphino) biphenyl (0.1 eq.) and DIEA (3.0 eq.).
PdCl.sub.2(0.05 eq.) 1,2- diethoxy-1,1,2,2-tetramethyl disilane
(1.1 eq.) 60.degree. C. 10 h. White solid; Yield: 26% Mol. Wt.:
507.70 MS (ES+): m/z = 508 [MH.sup.+], 530 [MH.sup.+ + Na] B-129 S-
Me ##STR00081## 1-methyl-2-pyrrolidinone (30 vol.),
2-(di-t-butylphosphino) biphenyl (0.1 eq.) and DIEA (3.0 eq.).
PdCl.sub.2(0.05 eq.) 1,2- diethoxy-1,1,2,2-tetramethyl disilane
(1.1 eq.) 60.degree. C. 10 h. White solid; Yield: (26%) Mol. Wt.:
514.75 MS (ES+): m/z = 515 [MH.sup.+] B-11 si ##STR00082##
1,2-diethoxy-1,1,2,2- tetarmethyl silane (3 eq.), PdCl2 (0.1 eq),
DTBPBP (0.2 eq), DIPEA (6 eq), NMP, 50.degree. C., 14 hrs. Yield
81.6%. Mol. Wt: 518.72 MS (ES+): m/z = 519.05 [MH.sup.+] B-148
##STR00083## 1,2-diethoxy-1,1-2,2- tetarmethyl silane (3 eq.),
PdCl2 (0.1 eq), DTBPBP (0.2 eq), DIPEA (6 eq), NMP, 50.degree. C.,
14 hrs. Yield 40%. Mol. Wt: 508.68 MS (ES+): m/z = 531.20 [MH.sup.+
+ Na] B-149 ##STR00084## 1,2-diethoxy-1,1-2,2- tetarmethyl silane
(3 eq.), PdCl2 (0.1 eq), DTBPBP (0.2 eq), DIPEA (6 eq), NMP,
50.degree. C., 14 hrs. Yield 60.6%. Mol. Wt: 524.75 MS (ES+): m/z =
547.35 [MH.sup.+ + Na] B-120F ##STR00085## 1,2-diethoxy-1,1-2,2-
tetarmethyl silane (3 eq.), PdCl.sub.2 (0.1 eq), DTBPBP (0.2 eq),
DIPEA (6 eq), NMP, 50.degree. C., 5 hrs. Yield 55%. Mol. Wt: 436.39
MS (ES+): m/z = 437.10 [MH.sup.+] B-129 ##STR00086##
1,2-diethoxy-1,1-2,2- tetarmethylsilane(3 eq.), PdCl2(0.1 eq),
DTBPBP(0.2 eq), DIPEA (6 eq), NMP, 50.degree. C., 5 hrs. Yield 25%.
Mol. Wt: 468.66 MS (ES+): m/z = 369 [MH.sup.+ - Boc], 719.30
[MH.sup.+ - Boc]
Step-3
Products of Step-2 were deprotected as per reaction conditions
mentioned in the table below to get the silanols. In most of the
cases, Compounds were found to be mixture of monomer & dimer as
per HPLC as well as NMR data. All reactions were done on 100-200 mg
scale.
TABLE-US-00012 Comp. Brief Reaction No. Structure conditions
Analytical data 62-Si ##STR00087## H.sub.3P0.sub.4 (6 eq.). in
dichloromethane. Stirring at room temp. for 12 hr. Quenched with
water, purification by prep. TLC (15% Methanol in chloroform)
Yield: 75% Mol Wt: 444.6, MS (ES+): m/z = 467 [MH.sup.+ + Na] HPLC
purity: 80% (220 nm). .sup.1H NMR (400 MHz, DMSO- d.sub.6 in 0.03%
TMS): .delta. 7.80- 7.67 (m, 5H), 7.64-7.53 (m, 5H), 7.50-7.11 (m,
4H), 4.64 (s, 1H), 3.68 (d, J = 4.3 Hz, 2H), 2.79 (t, J = 15.7 Hz,
5H), 1.68-1.40 (m, 4H), 0.04--0.20 (m, 6H). 35-Si ##STR00088##
H.sub.3P0.sub.4 (6 eq.). in dichloromethane. Stirring at room temp.
for 12 hr. DCM was decanted, Neutralization with 50% NaOH to pH ~ 8
extractions and purification by prep. TLC (15% Methanol in
chloroform Yield: 50%). MS (ES+): m/z = 467[MH.sup.+ + Na] HPLC:
(254 nm) 90.66% .sup.1H NMR (400 MHz, CD.sub.3CN): .delta. 7.57 (s,
1H), 7.44-7.05 (m, 8H), 6.99-6.77 (m, 4H), 5.13 (d, J = 5.4 Hz,
1H), 4.43 (s, 1H), 3.43 (d, J = 10.6 Hz, 2H), 2.92-2.76 (m, 2H),
2.51 (tq, = 9.7, 5.0 Hz, 3H), 1.66-1.55 (m, 2H), 1.48-1.31 (m, 2H),
0.12-0.03 (m, 6H) 152 N- Methyl ##STR00089## H.sub.3P0.sub.4 (2.5
eq.). in dichloromethane. Stirring at room temp. for 1 hr. Conc.
For removal of DCM, Neutralization with NaOH to pH ~ 8 extractions
and purification by prep. TLC (15% Methanol in chloroform White
solid; Yield: 39% Mol. Wt.: 421.61 (monomer) MS (ES+): m/z = 422
[MH.sup.+] (monomer), HPLC Purity: 89.59% .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.74-7.67 (m, 2H), 7.63 (s, 1H), 7.41 (d, J = 8.0 Hz,
1H), 7.35-7.29 (m, 2H), 7.26-7.19 (m, 2H), 4.64-4.48 (m, 2H), 3.90
(s, 5H), 3.25-3.10 (m, 2H), 2.96-2.84 (m, 1H), 1.84- 1.70 (m, 2H),
1.66-1.54 (m, 1H), 0.40 (s, 6H) 152 ##STR00090## H.sub.3P0.sub.4
(2.5 eq.). in dichloromethane. Stirring at room temp. for 1 hr.
Conc. For removal of DCM, Neutralization with NaOH to pH ~ 8
extractions and purification by prep. TLC (15% Methanol in
chloroform White solid; Yield: 46% Mol. Wt.: 407.58 (monomer),
796.40 (dimer), MS (ES+): m/z = 408 [MH.sup.+] (monomer), 819
[MH.sup.+ + Na] (dimer), HPLC Purity: 95.92% .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.75-7.60 (m, 3H), 7.42-7.20 (m, 5H), 4.65-4.48 (m,
2H), 3.96 (s, 2H), 3.25-3.10 (m, 2H), 2.98-2.85 (m, 1H), 1.85- 1.70
(m, 2H), 1.66-1.54 (m, 2H), 0.38 (s, 6H) 32-Si ##STR00091##
H.sub.3P0.sub.4 (2.5 eq.). in dichloromethane. Stirring at room
temp. For 1 hr. Conc. For removal of DCM, Neutralization with NaOH
to pH ~ 8 extractions and purification by prep. TLC (15% Methanol
in chloroform White solid; Yield: 18% Mol. Wt.: 407.58 (monomer),
796.40 (dimer), MS (ES+): m/z = 408 [MH.sup.+] (monomer), 819
[MH.sup.+ + Na] (dimer), HPLC Purity: 86.55% .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.49 (d, J = 8.0 Hz, 1H), 7.36- 7.18 (m, 6H), 7.06 (s,
1H), 4.80-4.70 (m, 2H), 3.91 (m, 2H), 3.60-3.46 (m, 1H), 3.02- 2.90
(m, 1H), 2.86-2.68 (m, 1H), 2.02-1.93 (m, 2H), 1.86- 1.75 (m, 2H),
0.44 (m, 6H) 129-S- Me ##STR00092## 1,4-dioxane (30 mL/g) conc. HCl
(1 mL/g) at room temp. 3 hrs, The reaction mixture was Concentrated
in vacuo and purified by preparative HPLC. Yield: 16%, Mol. Wt.:
414.64 (monomer), 811.26 (dimer) MS (ES+): m/z = 415 [MH.sup.+]
(monomer), 811 [MH.sup.+] (dimer) HPLC Purity: 82.95%, .sup.1H NMR
(400 MHz, CD.sub.3OD), monomer:dimer (48:34): 7.50- 7.16 (m, 7H),
4.82-4.70 (m, 1H), 4.10 (s, 2H), 3.94-3.70 (m, 1H), 3.04-2.85 (m,
2H), 2.51, 2.47 (2s, 6H, monomer + dimer), 2.05-1.54 (m, 4H), 0.38
(s, 3H) 11-Si ##STR00093## trifluroacetic acid (3, vol) DCM (50
vol), RT, 4 h. Yield 40%. Mol. Wt:- 418.60 (Monomer) 819.19(Dimer)
MS (ES+): m/z = 419.15 [MH.sup.+] (monomer) 841.45 [MH.sup.+ + Na]
(dimer) .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.01 (q, J =
26.6, 20.3 Hz, 2H), 7.64 (d, J = 40.2 Hz, 3H), 7.48 (d, J = 21.6
Hz, 1H), 7.27 (t, J = 17.9 Hz, 4H), 4.76 (d, J = 78.2 Hz, 1H), 3.97
(d, J = 22.4 Hz, 2H), 3.35-2.76 (m, 4H), 1.78 (m, 4H), 1.22 (s,
1H), 0.13-0.08 (m, 6H) 148 ##STR00094## trifluroacetic acid (2.5,
vol) DCM (50 vol), RT, 1 h. Yield 22%. Mol. Wt: 408.57 (Monomer)
799.12 (Dimer) MS (ES+): m/z = 409.20 [MH.sup.+] (monomer) 799.45
[MH.sup.+] (dimer) .sup.1H NMR (400 MHz, DMSO-d.sub.6, D.sub.2O):
.delta. 8.00-7.92 (m, 1H), 7.69-7.60 (m, 2H) 7.42-7.23 (m, 4H),
4.00 (s, 2H), 2.93-2.71 (m, 4H), 2.81 (t, J = 59.7 Hz, 1H),
1.83-1.61 (m, 4H), 0.40 (s, 6H). 149 ##STR00095## trifluroacetic
acid (2.5, vol) DCM(50 vol), RT, 2 h. Yield 4%. Mol. Wt: 424.63
(Monomer) 831.25(Dimer) MS (ES+): m/z = 425.15 [MH.sup.+] (Monomer)
831.40 [MH.sup.+] (dimer) .sup.1H NMR (400 MHz, DMSO-d.sub.6,
D.sub.2O): .delta. 7.94-7.86 (m, 1H), 7.28 (d, J = 9.2 Hz, 2H),
7.41- 7.34 (m, 5H) 4.02-3.92 (m, 2H), 2.94-2.67 (m, 5H), 1.86-1.53
(m, 4H), 0.39 (s, 6H) 120-F ##STR00096## THF: MeOH, KOH, Room
temperature, 2 hr Yield 55%. Mol. Wt: 436.59 (Monomer)
854.10(Dimer) MS (ES+): m/z = 437.25 [MH.sup.+] (Monomer) 855.15
[MH.sup.+] (Dimer) .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.21
(d, J = 9.7 Hz, 4H), 8.07- 7.97 (m, 1H), 7.80 (t, J = 8.0 Hz, 1H),
7.56 (dt, J = 14.3, 6.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 1H), 7.35 (t,
J = 6.6 Hz, 1H), 7.23 (t, J = 9.3 Hz, 1H), 4.69 (s, 1H), 4.02 (q, J
= 5.9, 5.5 Hz, 2H), 3.31-3.09 (m, 4H), 2.96 (s, 1H), 1.77 (d, J =
70.6 Hz, 4H), 0.47 (d, J = 29.2 Hz, 6H) 129 ##STR00097##
trifluroacetic acid (10, vol) DCM(20 vol), RT, 4 hr. Yield:- 11.45%
Mol. Wt: 368.54 MS (ES+): m/z = 369 [MH.sup.+] (monomer) 719.30
[MH.sup.+](dimer) HPLC Purity: (monomer) 47.85%, (dimer-) 49.42%
.sup.1H NMR (400 MHz, CD.sub.3CN, D.sub.2O): .delta. 7.61 (t, J =
3.5 Hz, 2H), 7.56 (s, 1H), 7.41 (d, J = 5.2 Hz, 2H), 7.32 (q, J =
4.0, 3.2 Hz, 1H), 7.26 (dd, J = 14.9, 6.1 Hz, 2H), 4.68 (s, 1H),
4.04 (d, J = 9.9 Hz, 2H), 3.80-3.60 (m, 1H),, 2.87 (t, J = 13.1 Hz,
3H), 1.65 (dd, J = 44.9, 28.5 Hz, 4H), 0.32 (d, J = 6.8 Hz,
6H).
Approach-2
Step-1
Bromo Esters were synthesized from the Bromo carboxylic acids (A1)
detailed description given above as per conditions mentioned in the
table. Details of the compounds synthesized are as below
TABLE-US-00013 Comp. Brief Reaction No. Structure conditions
Analytical data D-52 ##STR00098## thionyl chloride (1.2 eq),
ethanol, 60.degree. C., 5 hrs. Yield 70.5%. Mol. Wt:- 279.3 MS
(ES+): m/z = 279/281.3 [MH+], D-122 ##STR00099## WO2011/21209 A1,
2011 D-129- spiro ##STR00100## thionyl chloride (1.2 eq), Methanol,
60.degree. C., 5 hrs. Yield 71.5%. Mol. Wt:- 229.07 MS (ES+): m/z =
229/231.05 [MH.sup.+]
Step-2
Stirred suspension of suitably substituted ester of aryl bromo
carboxylic acid in N-methyl pyrrolidine was degassed with argon and
charged with palladium chloride, diisopropyl ethyl amine &
1,2-diethoxy-1,1,2,2, tetra methyl silane. Reaction mixture was
heated to .about.60.degree. C. and reaction monitored by LCMS till
most of the starting material was consumed. Reaction mixture is
then charged with acetonitrile, 1N aq. acetic acid and 2-(dimethyl
amino) ethane thiol hydrochloride stirred for 2 hr at room
temperature. Reaction mixture was then diluted with water, filtered
through celite, extracted with ethyl acetate and ethyl acetate
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo to get the crude products which were sufficiently pure to
be used for next step.
Required Bromo esters were synthesized by esterification of
corresponding bromo acids by refluxing with alcohol and thionyl
chloride. The details of bromo acids sourced/synthesised as per
literature methods/synthesised by adapted methods are given
below
TABLE-US-00014 Comp. Brief Reaction No. Structure conditions
Analytical data E-52 ##STR00101## 1,2-diethoxy-1,1-2,2- tetarmethyl
silane (3 eq.), PdCl2 (0.1 eq), DTBPBP (0.2 eq), DIPEA (6 eq), NMP,
50.degree. C., 14 hrs. Yield 44.5%. Mol. Wt: 274.39 MS (ES+): m/z =
274.95 [MH.sup.+] E-122 ##STR00102## 1-methyl-2-pyrrolidinone (30
vol.), 2-(di-t- butylphosphino) biphenyl (0.1 eq.) and DIEA (3.0
eq.). PdCl.sub.2(0.05 eq.) 1,2- diethoxy-1,1,2,2- tetramethyl
disilane (1.5 eq.) 60.degree. C. 12 h. Colorless oil, Yield: 48%,
Mol. Wt.: 224.33 (monomer), 430.64 (dimer) MS (ES+): m/z = 431
[MH.sup.+] (dimer) E-129- spiro ##STR00103## 1,2-diethoxy-1,1-2,2-
tetarmethyl silane (3 eq.), PdCl2 (0.1 eq), DTBPBP (0.2 eq), DIPEA
(6 eq), NMP, 50.degree. C., 14 hrs. Yield 71.5% Mol. Wt:- 224.33 MS
(ES+): m/z = 224.95 [MH.sup.+]
Step-3
Silanol esters from step-5 were hydrolyzed as per conditions
mentioned in the table below to get the aryl carboxy acids with
silanols functionality in the form of mixture of monomer and dimer.
Details of the compounds synthesized are as below
TABLE-US-00015 Comp. Brief Reaction No. Structure conditions
Analytical data F-52 ##STR00104## NaOH (6.00 eq.). In 1:1 mixture
of THF: Water (25 vol). Stirring at 50.degree. C. for 7 hrs. Conc.
For removal of THF, Acidified with KHSO.sub.4 to pH ~3 extraction
and concentration of organic solvent. TLC(20% Ethyl acetate in
n-Hexane) Yield 80.5%. Mol. Wt: 246.33 Ionization not observed in
LCMS, used as it is for next step, characterization done in next
coupling step Monitored on TLC and stained in bromo cresol. F-122
##STR00105## LiOH (3.00 eq.). in 1:1 mixture of THF:Water(25 vol).
Stirring at room temp. for 3 hrs. Conc. For removal of THF,
acidified with 2N HCl to pH ~2 extraction and concentration of
organic solvent. TLC (20% ethyl acetate in n-Hexane) Off-white
solid Yield: 65%, Monitored on TLC and stained in bromo cresol,
Mass not seen in ESMS, . silyl ester was characterized,
characterization done in next coupling step. F-129- spiro
##STR00106## NaOH (6.00 eq.). In 1:1 mixture of THF: Water (25
vol). Stirring at 50.degree. C. for 14 hrs. conc. For removal of
THF, acidified with KHSO.sub.4 to pH ~ 3 extractions and
concentration of organic solvent. TLC (20% ethyl acetate in
n-Hexane Yield 93.5%. Mol. Wt:- 196.28 Ionization not observed in
LCMS, used as it is for next step, characterization done in next
coupling step Monitored on TLC and stained in bromo cresol..
Step-4
Coupling of the carboxylic acids was carried out with protected
4-(3-Aminomethyl phenyl) piperidine as per conditions mentioned in
the table below.
TABLE-US-00016 Comp. Brief Reaction No. Structure conditions
Analytical data B-52- spiro ##STR00107## tert-butyl ((2H-
spiro[benzofuran-3,4'- piperidin]-5- yl)methyl)carbamate (1 eq.),
EDCI.HCl (1.5 eq.), DMAP (1.2 eq.), DCM(20 vol), RT, 4 h, Purified
by column chromatography Yield 93%. Mol. Wt: 546.73 MS (ES+): m/z =
547.20 [MH.sup.+] B-52 ##STR00108## 2,2,2-trifluoro-N-(3-
(piperidin-4- yl)benzyl)acetamide, (1 eq.), EDCI (1.5 eq.) DMAP
(1.5 eq.), DIEA (2 eq.) DCM (25 vol) R.T. 1 h; Yield 84% Mol. Wt:
514.61 MS(ES+): m/z = 537.10[MH.sup.+ + Na] B-122 ##STR00109##
4-(3-aminomethyl phenyl) piperidine, (1.2 eq.), EDCI (1.5 eq.) DMAP
(0.5 eq.), DCM R.T. 3 h; Colorless oil, Yield 23.25%, Mol. Wt.:
482.69(monomer), 947.36 (dimer). MS (ES+): m/z = 482 [MH.sup.++
Na](monomer), 947.6 [MH.sup.+](dimer) B-129- spiro ##STR00110##
tert-butyl-((2H-spiro [benzofuran-3, 4'- piperidin]-5-yl) methyl)
carbamate, (1. eq.), EDCI (1.5 eq.) DMAP (1.2 eq.), DCM R.T. 3 h
Yield 66% Mol. Wt:- 496.67 MS (ES+): m/z = 497.3 [MH.sup.+]
Step-5
Products of Step-7 were deprotected as per reaction conditions
mentioned in the table below to get the silanols. In most of the
cases, compounds were found to be mixture of monomer & dimer as
per HPLC as well as NMR data. All reactions were done on 100-200 mg
scale.
TABLE-US-00017 Comp. Brief Reaction No. Structure conditions
Analytical data 52-Spiro ##STR00111## trifluoro acetic acid (3
vol.). dichloromethane. Stirring at room temp for 3 hr. Conc. for
removal of DCM, and purification by prep HPLC. TLC (10% Methanol in
chloroform. Yield 30%. Mol. Wt: 446.60 (monomer) 875.2(dimer) MS
(ES+): m/z = 447.2 [MH.sup.+] (monomer) 875.55 [MH.sup.+](dimer)
.sup.1H NMR (400 MHz, DMSO- d.sub.6): .delta. 8.23 (s, 1H), 8.06
(d, J = 9.1 Hz, 4H), 7.80 (d, J = 6.9 Hz, 1H), 7.57 (t, J = 7.6 Hz,
2H), 7.36 (s, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.4 Hz,
1H), 4.46 (d, J = 50.2 Hz, 3H), 3.93 (q, J = 6.7, 6.2 Hz, 2H), 3.06
(s, 4H), 1.73 (s, 4H), 0.47 (d, J = 25.1 Hz, 6H). 52 ##STR00112##
THF: MeOH, KOH, at 50.degree. C. for 6 h, concentration followed by
extraction with ethyl acetate, and purification by prep HPLC. TLC
(10% Methanol in chloroform. Yield 10.4%. Mol. Wt: 418.60 (monomer)
819.20(dimer) MS (ES+): m/z = 419.15 [MH.sup.+] (monomer) 819.30
[MH.sup.+](dimer) .sup.1H NMR (400 MHz, CD.sub.3CN, D.sub.2O0):
.delta. 8.30 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8 Hz,
1H), 7.54 (m, 3H), 7.38-7.18 (m, 4H), 4.00 (s, 2H), 2.92-2.64 (m,
5H), 1.97- 1.40 (m, 4H), 0.47 (d, J = 25.1 Hz, 6H). 122
##STR00113## trifluoro acetic acid (6 eq.). in dichloromethane.
Stirring at room temp. for 12 hr. conc. for removal of DCM, and
purification by prep HPLC. TLC (10% Methanol in chloroform.
Colorless oil; Yield: 36% Mol. Wt.: 382.57 (monomer), 747.13
(dimer), MS (ES+): m/z = 383.15 [MH.sup.+] (monomer), 747.45
[MH.sup.+] (dimer), HPLC Purity: 99%(monomer + dimer) .sup.1H NMR
(400 MHz, DMSO- d.sub.6): .delta. 7.36-7.23 (m, 4H), 7.13-6.99 (m,
4H), 3.97 (d, J = 4.6 Hz, 2H), 3.12 (s, 2H), 2.91-2.72 (m, 3H),
2.08 (s, 2H), 1.69 (d, J = 113.7 Hz, 4H), -0.04--0.10 (m, 6H). 129-
Spiro ##STR00114## trifluoro acetic acid (2.5 vol.). in
dichloromethane. Stirring at room temp. for 3 hr. conc. for removal
of DCM, and purification by prep HPLC. TLC (10% Methanol in
chloroform. Yield 15%. Mol. Wt:- 396.55 (Monomer), 775.09(dimer) MS
(ES+): m/z = 419.15 [MH.sup.+ + Na] Monomer] 775.40 [MH.sup.+]
(dimer) .sup.1H NMR (400 MHz, DMSO- d.sub.6, D.sub.2O): .delta.
7.64-7.32 (m, 5H), 7.20 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.3 Hz,
1H), 4.42 (d, J = 44.6 Hz, 2H), 3.92 (d, J = 5.9 Hz, 2H), 3.28-2.90
(m, 4H), 1.74 (m, 4H), 0.29 (d, J = 22.5 Hz, 6H)
Approach-3 Step-1 & 2:--
Alkylation of Aryl hydroxyl carboxylates and subsequent hydrolysis
of aryl esters with dimethyl (aryloxymethyl) silanols functionality
was carried out as per conditions mentioned in the table below.
Carboxylic acids obtained after hydrolysis in the form of
mixture
TABLE-US-00018 Comp. No. Structure Brief Reaction conditions
Analytical data A1- 137 ##STR00115## 1) 4-hydroxy ethyl benzoate(1
eq), silane (eq), Potassium carbonate (eq), Acetone, 24 hrs reflux,
Product separated by column chromatography over silica gel 2) THF,
Water LiOH, Crude product used for next step after usual work-up
(Concentration, Acidification by KHSO.sub.4 & extraction with
ethyl acetate) Colorless oil Yield: 46.10%, HPLC: 95.35%, (mol. wt:
254) .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.24(d, J = 12 Hz,
6H), 2.74(s, 3H), 3.60(s, 2H), 3.88(s, 3H), 6.96(d, J = 8.8 Hz,
2H), 7.98(d, J = 8.4 Hz, 2H). 2)yellow color solid Yield: 78.83%,
ESMS: (mol. wt: 226) MS (ES+): m/z = 226.10 [MH.sup.+] ES.sup.+-,
(ES.sup.-)-225.44 [MH.sup.-] A1- 138 ##STR00116## 1) 3-hydroxy
ethyl benzoate(1 eq), silane (eq), Potassium carbonate (eq),
Acetone, 24 hrs reflux, Product separated by column chromatography
over silica gel 2) THF, Water LiOH, Crude product used for next
step after usual work-up (Concentration, Acidification by
KHSO.sub.4 & extraction with ethyl acetate) 1) colorless solid
Yield: 61.67%, HPLC: 99.25% .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.61 (d, J = 3.4 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.27-
7.23 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.59 (s, 3H),
0.23 (d, J = 11.5 Hz, 6H). 2) colorless solid Yield: -48.03% MS
(ES+): m/z = 226.19 [MH.sup.+] ES.sup.+-, (ES.sup.-)-225.18
[MH.sup.-] (mol. wt: 226)
Step-3
TABLE-US-00019 Comp. Brief Reaction No. Structure conditions
Analytical data B1-137 ##STR00117## Coupling of carboxylic acid
with Boc-protected 4-(3- aminomethyl phenyl) piperidine, (1.1 eq.),
EDCI (1.5 eq.) DMAP (0.5 eq.), DCM R.T. 12 h; Yield: 63.58% HPLC:
54.55% LCMS: (Mol Wt- monomer-470.28, Dimer-938.5), MS (ES+): m/z =
979.50 [MH.sup.+ + ACN] B1-138 ##STR00118## Coupling of carboxylic
acid with Boc-protected 4-(3- aminomethyl phenyl) piperidine, (1.1
eq.), EDCI (1.5 eq.) DMAP (0.5 eq.), DCM R.T. 12 h; Yield: 69.36%
HPLC: 28.52% LCMS: (Mol Wt- monomer-470.28, Dimer-938.5), MS (ES+):
m/z = 979.50 [MH.sup.+ + ACN]
Step-4
Products of Step-11 were deprotected as per reaction conditions
mentioned in the table below to get the silanols. In most of the
cases, Compounds were found to be mixture of monomer & dimer as
per HPLC as well as NMR data. All reactions were done on 100-200 mg
scale.
TABLE-US-00020 Comp. Brief Reaction No. Structure conditions
Analytical data 137 ##STR00119## trifluoro acetic acid (3 eq.). In
dichloromethane. Stirring at room temp. For 12 hr. conc. for
removal of DCM, and purification by prep HPLC. TLC (10% Methanol in
chloroform. Yield: 5.79% HPLC Purity: 89.63%, LCMS (dimer): (Mol.
Wt.; 778) MS (ES+): m/z = 779 [MH.sup.+] .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.15 (s, 3H), 7.41-7.18 (m, 6H), 6.99 (d, J
= 8.5 Hz, 2H), 4.02 (q, J = 5.6 Hz, 2H), 3.65 (s, 2H), 3.12-2.78
(m, 5H), 1.86-1.50 (m, 4H), 0.22 (s, 6H). 138 ##STR00120##
trifluoro acetic acid (3 eq.). In dichloromethane. Stirring at room
temp. For 12 hr. conc. for removal of DCM, and purification by prep
HPLC. TLC (10% Methanol in chloroform. Yield: 4.80% HPLC Purity:
85.35%, LCMS: (dimer): Mol. Wt.; 778, MS (ES+): m/z = 779
[MH.sup.+] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.11 (s,
3H), 7.40-7.25 (m, 4H), 6.98 (dt, J = 28.5, 5.4 Hz, 3H), 4.62 (s,
1H), 4.02 (q, J = 5.8 Hz, 2H), 3.63 (d, J = 8.8 Hz, 2H), 3.14 (d, 3
= 16.3 Hz, 4H), 2.95-2.75 (m, 1H), 1.73 (d, J = 87.2 Hz, 4H), 0.20
(d, J = 6.4 Hz, 6H)
Example 5
Diisopropylsilanol Synthesis
##STR00121##
Synthesis of
[4-[3-(aminomethyl)phenyl]-1-piperidyl]-[3-[hydroxy(diisopropyl)silyl]phe-
nyl]methanone
##STR00122##
A solution of
2,2,2-trifluoro-N-[[3-[1-[3-[hydroxy(diisopropyl)silyl]benzoyl]-4-piperid-
yl]phenyl]methyl]acetamide (0.014 g, 0.027 mmol) in MeOH (1 mL) was
charged with 1M KOH (0.081 mL, 0.081 mmol) and stirred at rt for 16
h. The reaction mixture was partitioned between DCM and H.sub.2O
and separated. The aqueous was re-extracted with DCM (3.times.) and
the combined organic fractions were dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo resulting in a crude off-white
foam solid. The crude was further purified by chromatography on
silica gel [ISCO Combiflash, 4 g gold cartridge, eluting with 100%
DCM.fwdarw.10% MeOH in DCM resulting in 1 mg of material.
Synthesis of
2,2,2-trifluoro-N-[[3-[1-[3-[hydroxy(diisopropyl)silyl]benzoyl]-4-piperid-
yl]phenyl]methyl]acetamide
##STR00123##
A solution of 3-[hydroxy(diisopropyl)silyl]benzoic acid (0.020 g,
0.0392 mmol), 2,2,2-trifluoro-N-[[3-(4-piperidyl)phenyl]methyl]
acetamide (0.027 g, 0.0950 mmol), TEA (0.017 mL, 0.119 mmol) in DCM
(1 mL) was charged with EDC (0.018 g, 0.0950 mmol) and HOBt (0.013
g, 0.0950 mmol) and stirred at rt under N.sub.2 gas for 4 hr. The
reaction mixture was partitioned between DCM and H.sub.2O and
separated. The aqueous was re-extracted with DCM (3.times.) and the
combined organic fractions were washed with sat. NaHCO3 (1.times.),
10% HCl (1.times.), brine (1.times.), dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo resulting in a crude oil which
was purified by chromatography on silica gel [ISCO Combiflash, 4 g
gold cartridge, eluting with 100% DCM.fwdarw.5% MeOH in DCM]
resulting in 14 mg, 34% yield of the title compound as an off-white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.57-7.63 (m,
2H), 7.38-7.48 (m, 2H), 7.33 (t, J=8.1 Hz, 1H), 7.13-7.21 (m, 3H),
6.86 (br.s., 1H), 4.85 (br. s., 1H), 4.50 (d, J=5.7 Hz, 2H), 3.85
(br. s., 1H), 2.71-3.20 (m, 2H), 1.50-2.05 (m, 6H), 1.13-1.30 (m,
2H), 1.04 (d, J=7.2 Hz, 6H), 0.954 (d, J=7.2 Hz, 6H).
Synthesis of 3-[hydroxy(diisopropyl)silyl]benzoic acid
##STR00124##
A solution of methyl 3-diisopropylsilylbenzoate (25 mg, 0.099 mmol)
in MeOH (500 .quadrature.L) was charged with 1M NaOH (100 mL, 0.099
mmol) and stirred at rt for 16 hr. The reaction mixture was
concentrated in vacuo to remove the MeOH and partitioned between
pet. ether and H.sub.2O and separated. The aqueous was acidified
with 10% HCl and extracted with EtOAc (3.times.). The combined
organic fractions were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo resulting in 21 mg, 88% yield of the title
compound as an off-white solid. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.32 (bs, 1H), 8.13 (dt, J=8.1, 1.5 Hz, 1H), 7.81 (dt,
J=7.2, 1.5 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 1.18-1.34 (m, 2H), 1.07
(d, J=7.5 Hz, 6H), 0.98 (d, J=7.5 Hz, 6H). MS (ES-): m/z 251.03
(100) [MH.sup.-].
Synthesis of methyl 3-diisopropylsilylbenzoate
##STR00125##
A solution of methyl-3-iodo benzoate (1.0 g, 3.82 mmol) in anhy.
THF (20 mL) was cooled to 5.degree. C. and dropwise charged with
iPrMgCl (2M in THF) (3.82 mL, 7.63 mmol) and stirred at 5.degree.
C. for an additional 3 hr. The reaction mixture was charged with
chlorodiisopropylsilane (3.26 mL, 19.1 mmol) and allowed to warm to
rt and stirred at this temperature for an additional 16 hr. The
reaction mixture was partitioned between EtOAc and sat. NaHCO.sub.3
and separated. The aqueous was re-extracted with EtOAc (3.times.)
and the combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo resulting in
a crude oil. The crude was further purified by chromatography on
silica gel [ISCO Combiflash, 4 g gold cartridge, eluting with 100%
pet. ether.fwdarw.30% EtOAc in pet ether] resulting in 100 mg, 10%
yield of the title compound as a clear colorless oil. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta.=8.18 (bs, 1H), 8.04 (dt, J=8.1, 1.5
Hz, 1H), 7.70 (dt, J=7.2, 1.5 Hz, 1H), 7.43 (t, J=7.2 Hz, 1H), 3.99
(t, J=3.3 Hz, 1H), 3.92 (s, 3H), 1.18-1.34 (m, 2H), 1.07 (d, J=7.5
Hz, 6H), 0.98 (d, J=7.5 Hz, 6H). MS (ES+): m/z 250.99 (100)
[MH.sup.+].
Example 6
Synthesis of Tryptase Inhibitors with Silanols Functionality
Seventeen Final targets with Silanol functionality were
synthesized. These compounds were synthesized by three different
approaches as given below.
Approach-1:--
Desired halo aryl carboxylic acids were first coupled with
protected 4-(3-Aminomethyl phenyl) piperidine or 5-Aminomethyl
Spiro [benzofuran-3, 4'-piperidine]. Coupled product was reacted
with 1,2-diethoxy-1,1,2,2-tetramethyldisilane to get
ethoxydimethyl(Aryl)silanes, which upon treatment with acetic acid
and subsequent deprotection afforded in the title compounds. 11
compounds were synthesized from Approach-1.
##STR00126## Approach-1
Step-1
Coupling of the aryl bromo carboxylic acids (A1) was carried out
with appropriate protected core as shown in the synthetic scheme as
per conditions mentioned in the table below.
TABLE-US-00021 1. 148 Spiro ##STR00127## 4 Apr. 2012 A-148Spiro
##STR00128## tert-butyl((2H- spiro[benzofuran-3,4'- piperidin]-5-
yl)methyl)carbamate, (1 eq.), EDCI (1.5 eq.) DMAP (1.2 eq.), DCM
(25 vol) R.T. 15 h; Yield: -97% Mol. Wt.: 541.43 MS (ES+): m/z =
541, 543 [MH.sup.+]
Step-2
Stirred suspension of coupled products from step-1 in N-methyl
pyrrolidine was degassed with argon and palladium chloride,
di-isopropyl ethyl amine, and 1,2-diethoxy-1,1,2,2, tetra methyl
silane were added to it. Reaction mixture was heated to
.about.60.degree. C. and reaction monitored by LCMS until most of
the starting material was consumed. There after acetonitrile, 1N
aq. acetic acid and 2-(dimethyl amino) ethane thiol hydrochloride
was added and reaction mixture stirred for 2 hr at room
temperature. Reaction mixture was diluted with water, filtered
through celite, extracted with ethyl acetate and the combined ethyl
acetate extracts were dried over sodium sulfate, filtered, and
concentrated in vacuo to get the crude products which were
sufficiently pure to be used for deprotection.
The details of the compounds are given below.
TABLE-US-00022 B-148 Spiro ##STR00129## 1,2-diethoxy-1,1-2,2-
tetramethyl silane(3 eq.) PdCl.sub.2 (0.1 eq), DTBPBP (0.2 eq),
DIPEA (6 eq), NMP, 50.degree. C., 14 hrs. Yield 35%. Mol. Wt:
536.69, MS (ES+): m/z = 558.9 [MH.sup.+ + Na]
Step-3
Products of Step-2 were deprotected as per reaction conditions
mentioned in the table below to get the silanols. In most of the
cases, Compounds were found to be mixture of monomer &dimer as
per HPLC as well as NMR data. All reactions were done on 100-200 mg
scale.
TABLE-US-00023 148 Spiro ##STR00130## trifluoroacetic acid (2.5,
vol) DCM (50 vol), RT, 1 h. Yield 10%. Mol. Wt: 436.58(Monomer)
855.14(Dimer) MS (ES+): m/z = 499.70 [MH.sup.+ + Na + AcN]
(monomer) 854.80[MH.sup.+] (dimer) .sup.1H NMR (400 MHz,
DMSO-d.sub.6, D.sub.2O): .delta. 8.01(br.s., 4H), 7.68 (d, J = 8.8
Hz, 1H), 7.63(s, 1H), 7.39-7.37(m, 2H), 7.23(d, J = 8.00 Hz, 1H),
6.84(d, J = 8.00 Hz, 1H), 4.49(s, 2H), 3.94(s, 2H), 3.13(br.s.,
3H), 1.38- 1.92(m, 5H), .0.42(s, 6H).
Example 7
The following table (Table 10) contains exemplary compounds. One of
ordinary skill in the art will recognize that these compounds may
be used to form homodimic or heterodimeric compounds.
TABLE-US-00024 TABLE 10 Exemplary Silyl Monomers Targeted to
Tryptase. Sr. Cmpd. No. Cmpd. Structure Code 1 ##STR00131## T130 2
##STR00132## T46-vinyl 3 ##STR00133## T48-vinyl 4 ##STR00134## T50
5 ##STR00135## T51 6 ##STR00136## T52 7 ##STR00137## T121 8
##STR00138## T122 9 ##STR00139## T93 10 ##STR00140## T94 11
##STR00141## T129 12 ##STR00142## T62 silyl 13 ##STR00143## T116
silyl 14 ##STR00144## T120 15 ##STR00145## T128 16 ##STR00146##
T148 17 ##STR00147## 18 ##STR00148## T149 19 ##STR00149## 20
##STR00150## 21 ##STR00151## 22 ##STR00152## 23 ##STR00153## 24
##STR00154## 25 ##STR00155## 26 ##STR00156## 27 ##STR00157##
T11Silyl 28 ##STR00158## 29 ##STR00159## 30 ##STR00160## 31
##STR00161## 32 ##STR00162## 33 ##STR00163## 34 ##STR00164## 35
##STR00165## T35Silyl 36 ##STR00166## T152NMeth- yl 37 ##STR00167##
T152 38 ##STR00168## T32Silyl 39 ##STR00169## T52Spiro 40
##STR00170## T120F 41 ##STR00171## T137 42 ##STR00172## T138 43
##STR00173## T129Spiro 44 ##STR00174## T129Smeth- yl 45
##STR00175## T148-spiro 46 ##STR00176## T52-spiro 47 ##STR00177##
T129-spiro 48 ##STR00178## 49 ##STR00179## 50 ##STR00180## 51
##STR00181## 52 ##STR00182## 53 ##STR00183## 54 ##STR00184## 55
##STR00185## 56 ##STR00186## 57 ##STR00187## 58 ##STR00188## 59
##STR00189## 60 ##STR00190## 61 ##STR00191## 62 ##STR00192## 63
##STR00193## 64 ##STR00194## 65 ##STR00195## 66 ##STR00196## 67
##STR00197## 68 ##STR00198## 69 ##STR00199## 70 ##STR00200## R =
-alkyl-aryl, -alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl,
-alkynyl-aryl, -alkynyl- heteroaryl, phenyl, or heteroaryl; wherein
phenyl and heteroaryl can be optionally substituted by halogen,
--CN, --OR, --SR, phenyl, or heteroaryl where phenyl or heteroaryl
can be optionally substituted by halogen, cyano, hydroxyl. 71
##STR00201## wherein A = O or S, n = 0 or 1; R = -alkyl-aryl,
-alkyl-heteroaryl, -alkenyl-aryl, -alkenyl- heteroaryl,
-alkynyl-aryl, -alkynyl-heteroaryl, phenyl, heteroaryl, where
phenyl and heteroaryl can be optionally substituted by halogen,
--CN, --OR, --SR, phenyl, or heteroaryl where phenyl or heteroaryl
can be optionally substituted by halogen, cyano, hydroxyl. 72
##STR00202## wherein A = O or S, n = 0 or 1; R = -alkyl-aryl,
-alkyl-heteroaryl, -alkenyl-aryl, -alkenyl- heteroaryl,
-alkynyl-aryl, -alkynyl-heteroaryl, phenyl, heteroaryl, where
phenyl and heteroaryl can be optionally substituted by halogen,
--CN, --OR, --SR, phenyl, or heteroaryl where phenyl or heteroaryl
can be optionally substituted by halogen, cyano, hydroxyl. 73
##STR00203## where n = 0 or 1; where A = S or O 74 ##STR00204##
where n = 0 or 1; where A = S or O 75 ##STR00205## 76 ##STR00206##
77 ##STR00207##
Example 8
The following table (Table 11) contains exemplary compounds that
target to the ribosome. In some embodiments, these compounds form
heterodimeric compounds.
TABLE-US-00025 TABLE 11 Exemplary Silyl Monomers Targeted to the
Ribosome. Sr. Cmpd. No. Cmpd. Structure Code 1 ##STR00208## 2
##STR00209## 3 ##STR00210## 4 ##STR00211## AzSi-1 5 ##STR00212##
Cl--Ph--Si-meta 6 ##STR00213## LZN-Si-3 7 ##STR00214## FFL-Si-3
Example 9
The following table (Table 12) contains exemplary ligand moieties
(i.e., X.sup.1, X.sup.2, or X.sup.3, and the like), where
##STR00215## indicates the attachment point to a connector moiety
(i.e., Y.sup.1, Y.sup.2, or Y.sup.3, and the like) or a silyl
moiety (i.e., Z.sup.1, Z.sup.2, or Z .sup.3, and the like) if the
connector moiety is absent.
TABLE-US-00026 TABLE 12 Exemplary Ligand Moieties Targeted to
Tryptase 1 ##STR00216## 2 ##STR00217## 3 ##STR00218## 4
##STR00219## 5 ##STR00220## 6 ##STR00221## 7 ##STR00222## where R'
is hydrogen, substituted or unsubstituted aliphatic, and
substituted or unsubstituted heteroaliphatic 8 ##STR00223## 9
##STR00224## 10 ##STR00225##
EQUIVALENTS
While specific embodiments have been discussed, the above
specification is illustrative and not restrictive. Many variations
will become apparent to those skilled in the art upon review of
this specification. The full scope of the embodiments should be
determined by reference to the claims, along with their full scope
of equivalents, and the specification, along with such
variations.
Unless otherwise indicated, all numbers expressing quantities of
ingredients, reaction conditions, and so forth used in the
specification and claims are to be understood as being modified in
all instances by the term "about." Accordingly, unless indicated to
the contrary, the numerical parameters set forth in this
specification and attached claims are approximations that may vary
depending upon the desired properties sought to be obtained.
SEQUENCE LISTINGS
1
9113PRTArtificialPeptide inhibitor of ERK
activationMISC_FEATURE(1)..(1)Residue 1 is stearated 1Met Pro Lys
Lys Lys Pro Thr Pro Ile Gln Leu Asn Pro1 5
10226PRTArtificialPeptide inhibitor of ERK activation 2Gly Tyr Gly
Arg Lys Lys Arg Arg Gln Arg Arg Arg Gly Met Pro Lys1 5 10 15Lys Lys
Pro Thr Pro Ile Gln Leu Asn Pro 20 2535PRTArtificialPeptide
inhibitor of B-Amyloid 3Lys Leu Val Phe Phe1
545PRTArtificialPeptide inhibitor of B-Amyloid 4Leu Val Phe Phe
Ala1 554PRTArtificialPeptide inhibitor of SH2
domainMISC_FEATURE(3)..(3)Xaa is Aib 5Glu Tyr Xaa
Asn166PRTArtificialPeptide inhibitor of SH2
domainMISC_FEATURE(1)..(1)residue 1 is
acetylatedMISC_FEATURE(2)..(2)Xaa is phosphotyrosine 6Ser Xaa Val
Asn Val Gln1 576PRTArtificialPeptide inhibitor of
phosphotyrosine-binding domainsMISC_FEATURE(6)..(6)Xaa is
phosphotyrosine, phosphonomethylphenylalanine,
difluorophosphonomethylphenylalanine, 0-malonyltyrosine, or 0-
fluoromalonyltyrosine 7Leu Ser Asn Pro Thr Xaa1
589PRTArtificialPeptide inhibitor of phosphotyrosine-binding
domainsMISC_FEATURE(9)..(9)Xaa is phosphotyrosine,
phosphonomethylphenylalanine, difluorophosphonomethylphenylalanine,
0-malonyltyrosine, or 0- fluoromalonyltyrosine 8Leu Tyr Ala Ser Ser
Asn Pro Ala Xaa1 5910PRTArtificialPeptide inhibitor of SH3 domain
9Val Pro Pro Pro Val Pro Pro Arg Arg Arg1 5 10
* * * * *